23. carbonyl condensation reactions
TRANSCRIPT
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Chapter 23
Carbonyl Condensation
Reactions
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Condensation Reactions
Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions
Combines both nucleophilic and –substitution steps
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Why this Chapter?
Carbonyl condensation reactions also occur
often in metabolic pathw ays.
Also, one of the general methods used to form
new C-C bonds.
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Carbonyl Condensation: The Aldol Reaction
Acetaldehy de reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldehy de
The b-hy droxy aldehy de product is aldol (aldehy de + alcohol)
This is a general reaction of aldehy des and ketones
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The Equilibrium of the Aldol
The aldol reaction is reversible, favoring the
condensation product only for aldehydes w ith no
substituent
Steric factors are increased in the aldol product
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Aldehydes and Ketones and the Aldol Equilibrium
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Mechanism of Aldol Reactions
Aldol reactions, like all carbony l condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbony l group of the
acceptor molecule
The addition intermediate is protonated to giv e an
alcohol product
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Carbonyl Condensation versus Alpha-Substitution
Carbonyl condensations and -substitutions both involve f ormation of the enolate ion intermediates
Alpha-substitution reactions are accomplished by converting all of the carbonyl compound to enolate form so it is not an electrophile
Immediate addition of an alkyl halide completes the alkylation reaction
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Conditions for Condensations
A small amount (cataly tic amount) of base is used to generate a small amount of enolate in the presence of unreacted carbony l compound
Af ter the condensation, the basic cataly st is regenerated
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Dehydration of Aldol Products: Synthesis of Enones
The b-hy droxy carbony l products dehy drate to y ield conjugated enones
The term “condensation” ref ers to the net loss of water and combination of 2 molecules
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Dehydration of β-Hydroxy Ketones and
Aldehydes
The hy drogen is remov ed by a base, y ielding an enolate ion that expels the –OH leav ing group
Under acidic conditions the –OH group is protonated and water is expelled
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Driving the Equilibrium
Remov al of water f rom the aldol reaction mixture can be used to driv e the reaction toward products
Ev en if the initial aldol f av ors reactants, the subsequent dehy dration step pushes the reaction to completion
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Using Aldol Reactions in Synthesis
If a desired molecule contains either a b-hydroxy carbonyl or a conjugated enone, it might come from an aldol reaction
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Extending the Synthesis
Subsequent transformations can be carried out on the aldol products
A saturated ketone might be prepared by catalytic hy drogenation of the enone product
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Mixed Aldol Reactions
A mixed aldol reaction betw een tw o similar aldehyde or ketone partners leads to a mixture of four possible products
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Mixed Aldol Condensations
Single Mixed Aldol Product
If one of the carbonyl partners contains no hydrogens and the carbonyl is unhindered (such as benzaldehyde and f ormaldehyde) it is a good electrophile and can react with enolates, then a mixed aldol reaction is likely to be successful
2-methylcyclohexanone gives the mixed aldol product on reaction with benzaldehyde
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Single Mixed Aldol Condensations
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Mixed Aldols With Acidic Carbonyl Compounds
Ethy l acetoacetate is completely conv erted into its enolate ion under less basic conditions than monocarbony l partners
Aldol condensations with ethy l acetoacetate occur pref erentially to giv e the mixed product
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Retrosynthesis of Aldol
Condensation
Practice I:21
(1) Which of the following compounds can be prepared as a single product in a mixed aldol reaction?
(2) Show the reactants that will combine to give each compound.
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Intramolecular Aldol Reactions
Treatment of certain dicarbony l compounds with base produces cy clic products by intramolecular reaction
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Mechanism of IntramolecularAldolReactions
Both the nucleophilic carbony l anion donor and the electrophilic carbony l acceptor are now in the same molecule.
The least strained product is f ormed because the reaction is rev ersible
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Intramolecular Cyclization
Reaction
Intramolecular aldol reactions of diketones are of ten used f or making f iv e- and six-membered ringed compounds
Rings smaller or larger than f iv e or six members are not f av ored due to ring strain or entropy
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Practice II:
What product w ould you expect from the base
treatment of 1,6-cyclodecanedione
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The Claisen Condensation Reaction
Reaction of an ester having an hydrogen w ith 1 equivalent of a base to yield a b-keto ester
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Synthesis of acetoacetic ester
Mechanism of the Claisen
Condensation
Similar to aldol condensation: nucleophilic acy l substitution of an ester enolate ion on the carbony l group of a second ester
molecule
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Features of the Claisen Condensation
If the starting ester has more than one acidic
hydrogen, the product b-keto ester has a doubly
activated proton that can be abstracted by base
Requires a full equivalent of base rather than a
catalytic amount
The deprotonation drives the reaction to the
product
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Propose a mechanism for the self-condensation of ethyl acetate to give ethyl acetoacetate.
The first step is formation of the ester enolate. The equilibrium for this step lies far to the
left; ethoxide deprotonates only a small fraction of the ester.
The enolate ion attacks another molecule of the ester; expulsion of ethoxide ion gives ethyl
acetoacetate.
Solved Problem I
Solution
In the presence of ethoxide ion, ethyl acetoacetate is deprotonated to give its enolate. This exothermic
deprotonation helps to drive the reaction to completion.
When the reaction is complete, the enolate ion is reprotonated to give ethyl acetoacetate.
Solved Problem I (Continued)
Solution (Continued)
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Show what ester would undergo a self-claisen condensation to give the following b-keto ester.
First, break the structure apart at the , b bond (, b to the ester carbonyl). This is the bond formed in
the Claisen condensation.
Solved Problem II
Solution
Next, replace the proton that was lost, and replace the alkoxy group that was lost from the carbonyl.
Two molecules of methyl 3-phenylpropionate result.
Now draw out the reaction. Sodium methoxide is used as the base because the reactants are methyl
esters.
Solved Problem II(Continued)
Solution (Continued)
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Mixed Claisen Condensation
Tw o different esters can be used, but one
ester should have no hydrogens.
Useful esters are benzoates, formates,
carbonates, and oxalates.
Ketones (pKa = 20) may also react w ith an
ester to form a b-diketone.
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Mixed Claisen Condensations
Successful w hen one of the tw o esters acts as the electrophilic acceptor in reactions w ith other ester anions to give mixed b-keto esters
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Mixed Claisen Condensation with
Ketones and Esters
Mixed Claisen condensation between ketones and esters are also possible.
Ketones are more acidic than esters, and the ketone component is more likely to deprotonate and serv e as the enolate component in the condensation.
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Ketones and Esters
The ketone enolate attacks the ester, w hich
undergoes nucleophilic acyl substitution, and
thereby, acylates the ketone.
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Ketones and Esters
Reactions betw een ketones and esters results in the formation of b-diketones
Best w hen the ester component has no hydrogens and can't act as the nucleophilic donor
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Intramolecular Claisen Condensations: The Dieckmann Cyclization
Intramolecular Claisen condensation
Best with 1,6-diesters (product: 5-memberedb-ketoester) and 1,7-diesters (product: 6-membered b-ketoester)
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Mechanism of the Dieckmann Cyclization
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Alkylation of Dieckmann Product
The cyclic b-keto ester can be further alkylated and decarboxylated as studied in the acetoacetic ester synthesis
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Conjugate Carbonyl Additions:
The Michael Reaction
,b-unsaturated carbony l compounds hav e unusually electrophilic double bonds.
The b-carbon is electrophilic because it shares the partial positiv e charge of the carbony l carbon through resonance.
Conjugate Carbonyl Additions: The Michael Reaction
Enolates can add as nucleophiles to ,b-unsaturated aldehydes and ketones to give the conjugate addition product
More like Aldol products reacting w ith the product from the claisen condensation/Dieckmann reaction
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Best Conditions for the Michael Reaction
Enolate from a b-keto ester or other 1,3-dicarbonyl compound adding to an unhindered ,b-unsaturated ketone
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Mechanism of the Michael
Reaction Nucleophilic
addition of an enolate ion donor to the b carbon of an ,b-unsaturated carbony l acceptor
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Generality of the Michael Reaction Occurs with a variety of ,b-unsaturated carbonyl compounds
(aldehy des, esters, amides), ,b-unsaturated nitriles and nitro compounds
Donors include b-diketones, b-keto esters, malonic esters, b-keto nitriles, and nitro compounds
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Show how the following diketone might be synthesized using a Michael addition.
A Michael addition would have formed a new bond at the b carbon of the acceptor. Therefore,
we break this molecule apart at the b,g bond.
Solved Problem
Solution
Carbonyl Condensations with Enamines:
The Stork Reaction
Enamines are equiv alent to enolates in that their reactions and can be used to accomplish the transf ormations under milder conditions
Enamines are prepared f rom a ketone and a secondary amine
(recall: chapter 19)
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Enamines Are Nucleophilic
Ov erlap of the nitrogen lone-pair orbital with the double-bond π orbitals increases electron density on the carbon atom
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Enamine Addition and
Hydrolysis Enamine adds to an ,b-unsaturated carbonyl
acceptor
The product is hydrolyzed to a 1,5-dicarbonyl compound
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The Robinson Annulation Reaction
A tw o-step process: combines a Michael reaction w ith an intramolecular aldol reaction
The product is a substituted 2-cyclohexenone
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Robinson: Mechanism
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Robinson: Mechanism
Some Biological Carbonyl Condensation Reactions
Malony l ACP is decarboxy lated and enolate is f ormed
Enolate is added to the carbony l group of another acy l group through a thioester linkage to a sy nthase
Tetrahedral intermediate giv es acetoacety l ACP
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Problem
In a mixed Claisen reaction of cyclopentanone
w ith ethyl formate, a much higher yield of the
desired product is obtained by f irst mixing the
tw o carbonyl components and then adding base,
rather than by f irst mixing base w ith
cyclopentanone and then adding ethyl formate.
Explain.
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Answer
If cyclopentanone and base are mixed f irst, aldol
self-condensation of cyclopentanone (Aldol
product) can occur before ethyl formate is
added. If both carbonyl components are mixed
together before adding base, the more favorable
mixed Claisen condensation occurs w ith less
competition from the aldol self -condensation
reaction.
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