Chapter 19

Question 1

formation of an enolate anion

Answer 1

•Enolate anions are formed by treating an aldehyde, ketone, or ester, each of which has at least one alpha-hydrogen, with base,
–Most of the negative charge in an enolate anion is on oxygen.

Question 2

enolate anions

Answer 2

•Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions,

Question 3

aldol reaction

Answer 3

•The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound.
–Although these reactions may be catalyzed by either acid or base, base catalysis is more common.
•The product of an aldol reaction is:–a beta-hydroxyaldehyde.
–Intramolecular aldol reactions are most successful for formation of five- and six-membered rings.

Question 4

aldol reaction base catalyzed

Answer 4

Step 1: Formation of a resonance-stabilized enolate anion.
Step 2: Carbonyl addition gives a TCAI.
Step 3: Proton transfer to O- completes the aldol reaction.The Aldol Reaction: Base Catalyzed

Question 5

aldol reaction acid catalyzed

Answer 5

–Step 1: Acid-catalyzed equilibration of keto and enol forms.
–Step 2: Proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone.
–Step 3: Attack of the enol of one molecule on the protonated carbonyl group of another molecule.
–Step 4: Proton transfer to A- completes the reaction.

Question 6

Aldol Products

Answer 6

–Aldol products are very easily dehydrated to alpha,beta-unsaturated aldehydes or ketones.
–Aldol reactions are reversible and often little aldol is present at equilibrium.
–Keq for dehydration is generally large.
–If reaction conditions bring about dehydration, good yields of product can be obtained.

Question 7

crossed aldol reactions

Answer 7

•In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group
•Crossed aldol reactions are most successful if
–one of the reactants has no alpha-hydrogen and, therefore, cannot form an enolate anion, and
–the other reactant has a more reactive carbonyl group, namely an aldehyde.

Question 8

Henry Reaction (also crossed aldol)

Answer 8

•Nitro groups can be introduced by way of an aldol reaction using a nitroalkane.
–Nitro groups can be reduced to 1° amines.

Question 9

Claisen Condensation

Answer 9

•Esters also form enolate anions which participate in nucleophilic acyl substitution.
–The product of a Claisen condensation is a beta-ketoester.
–Claisen condensation of ethyl propanoate gives this beta-ketoester.
-the Claisen condensation uses up one equivalent of base.Therefore, the alpha-position (next to the carbonyl) must have at least one protonAlso, notice how one of the products is ethanol in this instance.

Question 10

steps to claisen condensation

Answer 10

Step 1: Formation of an enolate anion.
Step 2: Attack of the enolate anion on a carbonyl carbon gives a TCAI.
Step 3: Collapse of the TCAI gives a -ketoester and an alkoxide ion.
Step 4: An acid-base reaction drives the reaction to completion.

Question 11

Dieckman Condensation

Answer 11

•An intramolecular Claisen condensation

-The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.

Question 12

crossed claisen condensation

Answer 12

•Crossed Claisen condensations between two different esters, each with alpha-protons, give mixtures of products and are not useful.
–Useful crossed Claisen condensations are possible, however, if there is an appreciable difference in reactivity between the two esters; that is, when one of them has no alpha-hydrogens.
–The ester with no alpha-hydrogen atoms is generally used in excess.

Question 13

enamines

Answer 13

•Enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone.–The 2° amines most commonly used to prepare enamines are pyrrolidine and morpholine.

Question 14

examines-alkylation

Answer 14

•The value of enamines is that the -carbon is nucleophilic. (They act like nitrogen enols.)
–Enamines undergo SN2 reactions with methyl and 1° haloalkanes, alpha-haloketones, and alpha-haloesters.
–Treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide.
–Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone.

Question 15

enamines - acylation

Answer 15

–Enamines undergo acylation when treated with acid chlorides and acid anhydrides.

Question 16

acetoacetic ester synthesis

Answer 16

•The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones
–Step 1: Formation of the enolate anion of AAE.
–Step 2: Alkylation with allyl bromide.
–Steps 3 & 4 Saponification followed by acidification.
–Step 5: Thermal decarboxylation.
To prepare a disubstituted acetone, treat the monoalkylated AAE with a second mole of base, etc.

Question 17

Masonic ester synthesis

Answer 17

–The strategy of a malonic ester (ME) synthesis is identical to that of an acetoacetic ester synthesis, except that the starting material is a -diester rather than a -ketoester. Also, the product is an acid.
–Treat malonic ester with an alkali metal alkoxide.
–Saponify and acidify.

Question 18

Enolates of Unsymmetrical Carbonyl Compounds

Answer 18

•When an unsymmetrical carbonyl compound like 2-methylcyclohexanone is treated with base, two enolates are possible.

Question 19

A kinetic enolate is favored by:

Answer 19

• A strong nonnucleophilic base—a strong base (in slight excess) ensures that the enolate is formed rapidly. A bulky base like LDA removes the more accessible proton on the less substituted carbon much faster than a more hindered proton.
• Polar aprotic solvent—the solvent must be polar to dissolve the polar starting materials and intermediates. It must be aprotic so that it does not protonate any enolate that is formed.
• Low temperature—the temperature must be low (-78°C) to prevent the kinetic enolate from equilibrating to the thermodynamic enolate.

Question 20

A thermodynamic enolate is favored by:

Answer 20

•A strong base—A strong base yields both enolates, but in a protic solvent (see below), enolates can also be protonated to re-form the carbonyl starting material. At equilibrium, the lower energy intermediate always wins out so that the more stable, more substituted enolate is present in a higher concentration. This can be done by using the ketone in excess or through the use of protic bases.
•Common bases are Na+ ̄OCH2CH3, K+ ̄OC(CH3)3, or other alkoxides.
•A protic solvent (CH3CH2OH, t-BuOH, or other alcohols).
•Room temperature (25°C).
•Thermodynamic versus kinetic control.
•Addition of the nucleophile is irreversible for strongly basic carbon nucleophiles.
–Enamines also participate in Michael reactions.

Question 21

Michael reaction

Answer 21

–The double bond of an alpha,beta-unsaturated carbonyl compound is activated for nucleophilic attack.
•Michael reaction: The nucleophilic addition of an enolate anion to an alpha,beta-unsaturated carbonyl compound.
-Generalized Michael reaction: Addition of other nucleophiles to alpha,beta-unsaturated carbonyl compounds.

Question 22

mechanism of Michael reaction

Answer 22

Step 1: Proton transfer to a base to generate an anion.
Step 2: Addition of Nu:- to the  carbon of the ,-unsaturated carbonyl compound.
Step 3: Proton transfer to HB gives an enol.
Step 4: Tautomerism of the less stable enol form to the more stable keto form.

Question 23

key point of Michael reaction

Answer 23

•A key point about nucleophilic addition to ,-unsaturated carbonyl compounds:
–Resonance-stabilized enolate anions and enamines are weak bases, react slowly with alpha,beta-unsaturated carbonyl compounds, and give 1,4-addition products.
–Organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and given primarily 1,2-addition.

Question 24

Gilman Reagents

Answer 24

•Gilman reagents undergo conjugate addition to ,-unsaturated aldehydes and ketones in a reaction closely related to the Michael reaction.
–Gilman reagents are unique among organometallic compounds in that they give almost exclusively 1,4-addition.
–Other organometallic compounds, including Grignard reagents, add to the carbonyl carbon by 1,2-addition

Question 25

Robinson Annulation: Michael-Aldol Combination

Answer 25

•The Robinson annulationis a ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction.
•The starting materials for a Robinson annulation are an alpha,beta-unsaturated carbonyl compound and an enolate.
•The Robinson annulation forms a six-membered ring and three new C—C bonds—two sigma bonds and one pi bond.•
The product contains an alpha,beta-unsaturated ketone in a cyclohexane ring—that is, a 2-cyclohexenone.
•To generate the enolate component of the Robinson annulation, ̄OH in H2O or ̄OEt in EtOH are typically used.
•The Robinson annulation consists of two parts: a Michael addition to the alpha,beta-unsaturated carbonyl compound, followed by an intramolecular aldol condensation.
•In part two of the mechanism, an intramolecular aldol reaction is followed by dehydration to form a six-membered ring.

Question 26

Crossed Enolate Reactions using LDA

Answer 26

•With a strong enough base, enolate anion formation can be driven to completion.
•The base most commonly used for this purpose is lithiumdiisopropylamide, LDA.
•LDA is prepared by dissolving diisopropylamine in THF and treating the solution with butyl lithium.
•Using a molar equivalent of LDA, one can completely convert an aldehyde, ketone or ester to its corresponding enolate anion.
•The crossed aldol reaction between acetone and an aldehyde can be carried out successfully by adding acetone to one equivalent of LDA to preform its enolate anion, Then, treat with the aldehyde
•For ketones with two sets of nonequivalent alpha-hydrogens, is formation of the enolate anion regioselective?
–The answer is that a high degree of regioselectivity exists and that it depends on experimental conditions
•The most important factor determining the composition of the enolate anion mixture is whether the reaction is under kinetic (rate) or thermodynamic (equilibrium) control.
•Thermodynamic Control: Experimental conditions that permit establishment of equilibrium between two ormore products of a reaction. The composition of the mixture is determined by the relative stabilities of the products.
–Equilibrium among enolate anions is established when the ketone is in slight excess, a condition under which it is possible for proton-transfer reactions to occur between an enolate and an -hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions.
•Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product.
–In the case of enolate anion formation, kinetic control refers to the relative rate of removal of alternative -hydrogens.
–With the use of a strong, bulky base, the less hindered hydrogen is removed more rapidly, and the major product is the less substituted enolate anion.
–No equilibrium among alternative structures is set up
•It is possible to form regioselectively one or the other enolate by the proper use of reaction conditions, because the base, solvent and reaction temperature all affect the identity of the enolate formed.•The kinetic enolate forms faster, so strongly basic reaction conditions favor it over slower processes with higher energies of activation.•The kinetic enolate is the less stable enolate, so it must not be allowed to equilibrate to the more stable thermodynamic enolate. •In practice, this means using lower temperatures and avoiding proton sources (since that favors deprotonated keto-enolate interconversion and hence equilibration).

Question 27

Acetyl Coenzyme A

Answer 27

•Carbonyl condensations are among the most widely used reactions in the biological world for formation of new carbon-carbon bonds in such biomolecules as
–fatty acids.
–cholesterol, bile acids, and steroid hormones.
–terpenes
.•One source of carbon atoms for the synthesis of these biomolecules is acetyl coenzyme A (acetyl-CoA).

Question 28

claisen condensation of Acetyl-CoA

Answer 28

–Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase.
–This is followed by an aldol reaction with a second molecule of acetyl-CoA and hydrolysis.
–Enzyme-catalyzed reduction of the thioester group.
–Phosphorylation by ATP followed by beta-elimination.
–Isopentenyl pyrophosphate has the carbon skeleton of isoprene and is a key intermediate in the synthesis of these classes of biomolecules.

Question 29

Enolates of Unsymmetric Ketones

Answer 29

–When 2-methylcyclohexanone is treated with a slight excess of LDA, the enolate is almost entirely the less substituted enolate anion.