Chapter 19 Flashcards
(29 cards)
formation of an enolate anion
•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.
enolate anions
•Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions,
aldol reaction
•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.
aldol reaction base catalyzed
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
aldol reaction acid catalyzed
–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.
Aldol Products
–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.
crossed aldol reactions
•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.
Henry Reaction (also crossed aldol)
•Nitro groups can be introduced by way of an aldol reaction using a nitroalkane.
–Nitro groups can be reduced to 1° amines.
Claisen Condensation
•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.
steps to claisen condensation
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.
Dieckman Condensation
•An intramolecular Claisen condensation
-The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.
crossed claisen condensation
•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.
enamines
•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.
examines-alkylation
•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.
enamines - acylation
–Enamines undergo acylation when treated with acid chlorides and acid anhydrides.
acetoacetic ester synthesis
•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.
Masonic ester synthesis
–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.
Enolates of Unsymmetrical Carbonyl Compounds
•When an unsymmetrical carbonyl compound like 2-methylcyclohexanone is treated with base, two enolates are possible.
A kinetic enolate is favored by:
- 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.
A thermodynamic enolate is favored by:
•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.
Michael reaction
–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.
mechanism of Michael reaction
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.
key point of Michael reaction
•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.
Gilman Reagents
•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