ch22 - Laney College4/25/2012 4 • When a proton is alpha to two different carbonyl groups, its...

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• For carbonyl compounds, Greek letters are often used to describe the proximity of atoms to the carbonyl center.

22.1 Introduction to Alpha Carbon Chemistry – Enols and Enolates

• This chapter will primarily explore reactions that take place at the alpha carbon.

Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e22-1

• The reactions we will explore proceed though either an enol or an enolate intermediate.



• Trace amounts of acid or base catalyst provide equilibriums in which both the enol and keto forms are present.


• How is equilibrium different from resonance?

• At equilibrium, > 99% of the molecules exist in the keto form. WHY?


• In rare cases such as the example below, the enol form is favored in equilibrium.


• Give two reasons to explain WHY the enol is favored.

• The solvent can affect the exact percentages.


• Phenol is an example where the enol is vastly favored over the keto at equilibrium. WHY?



• The mechanism for the tautomerization depends on whether it is acid catalyzed or base catalyzed.



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• The mechanism for the tautomerization depends on whether it is acid catalyzed or base catalyzed.



• As the tautomerization is practically unavoidable, some fraction of the molecules will exist in the enol form.

• Analyzing the enol form, we see there is a minor (but significant) resonance contributor with a nucleophilic

b


carbon atom.

• Practice with CONCEPTUAL CHECKPOINTs 22.1 through 22.3.


• In the presence of a strong base, an ENOLATE forms.


• The enolate is much more nucleophilic than in the enol. WHY?


• The enolate can undergo C‐attack or O‐attack.

• Enolates generally undergo C‐attack. WHY?



• Alpha protons are the only protons on an aldehyde or ketone that can be removed to form an enolate.


• Removing the aldehyde proton, or the beta or gamma proton, will NOT yield a resonance stabilized intermediate.

• Practice with SKILLBUILDER 22.1.Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e22-11

• Draw all possible enolates that could form from the following molecule.


O


O O

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• Why would a chemist want to form an enolate?

• To form an enolate, a base must be used to remove the alpha protons.


• The appropriate base depends on how acidic the alpha protons are .

• What method do we have to quantify how acidic something is?


• Let’s compare some pKa values for some alpha protons.



• When pKa values are similar, both products and


p a , preactants are present in significant amounts.

• Which side will this equilibrium favor?


• In this case, it is an advantage to have both enolate and aldehyde in solution so they can react with one another.


• Show how the electrons might move in the reaction between the enolate and the aldehyde.


• If you want the carbonyl to react irreversibly, a stronger base, such as H–, is necessary.


• When is it synthetically desirable to convert all of the carbonyl into an enolate?


• Lithium diisopropylamide (LDA) is an even stronger base that is frequently used to promote irreversible enolate formation.


• Why is the reaction affectively irreversible?

• LDA features two bulky isopropyl groups. Why would such a bulky base be desirable?


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• When a proton is alpha to two different carbonyl groups, its acidity is increased.


• Draw the resonance contributors that allow 2,4‐pentanedione to be so acidic.


• 2,4‐pentanedione is acidic enough that hydroxide or alkoxides can deprotonate it irreversibly.


• Figure 22.2 summarizes the relevant factors you should consider when choosing a base.



• H3O+ catalyzes the keto enol tautomerism. HOW?• The enol tautomer can attack a halogen molecule.

22.2 Alpha Halogenation of Enols and Enolates

• The process is AUTOCATALYTIC:– The regenerated acid can catalyze another tautomerization

and halogenation.


• When an unsymmetrical ketone is used, bromination occurs primarily at the more substituted carbon.


• The major product results from the more stable (more substituted) enol.

• A mixture of products is generally unavoidable.


• This provides a two‐step synthesis for the synthesis of an α,β‐unsaturated ketone.


• Give a mechanism that shows the role of pyridine.

• Other bases, such as potassium tert‐butoxide, can also be used in the second step.

• Practice with CONCEPTUAL CHECKPOINTs 22.9 and 22.10.


• The Hell‐Volhard Zelinsky reaction brominates the alpha carbon of a carboxylic acid.


• PBr3 forms the acyl bromide, which more readily forms the enol and attacks the bromine.

• Hydrolysis of the acyl bromide is the last step.

• Draw a complete mechanism.

• Practice CONCEPTUAL CHECKPOINTs 22.11 and 22.12.


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• Alpha halogenation can also be achieved under basic conditions.


• The formation of the enolate is not favored, but the equilibrium is pushed forward by the second step.

• Will the presence of the α bromine make the remaining α proton more or less acidic?


• Monosubstitution is not possible. WHY?

• Methyl ketones can be converted to carboxylic acids using excess halogen and hydroxide.


• Once all three α protons are substituted, the CBr3 group becomes a decent leaving group.


• Once all three α protons are substituted, the CBr3 group becomes a decent leaving group.

• The last step is practically irreversible WHY?


• The last step is practically irreversible. WHY?


• The carboxylate produced on the last slide can be protonated with H3O+.

• The reaction works well with Cl2, Br2, and I2, and it is known as the haloform reaction.


• The iodoform reaction may be used to test for methyl ketones, because iodoform can be observed as a yellow solid when it forms.



• Give the major product for the reaction below. Be careful of stereochemistry.



• Recall that when an aldehyde is treated with hydroxide (or alkoxide), an equilibrium forms where significant amounts of both enolate and aldehyde are present.

• If the enolate attacks the aldehyde, an aldol reaction

22.3 Aldol Reactions

occurs.

• The product features both aldehyde and alcohol groups.

• Note the location of the –OH group on the beta carbon.


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• The aldol mechanism:



• The aldol reaction is an equilibrium process that generally favors the products:


• How might the temperature affect the equilibrium?


• A similar reaction for a ketone generally does NOT favor the β‐hydroxy ketone product.


• Give a reasonable mechanism for the retro‐aldol reaction.

• Practice with SKILLBUILDER 22.2.


• Predict the products for the follow reaction, and give a reasonable mechanism. Be careful of stereochemistry.



• When an aldol product is heated under acidic or basic conditions, an α,β‐unsaturated carbonyl forms.


• Such a process is called an ALDOL CONDENSATION, because water is given off.

• The elimination reaction above is an equilibrium, which generally favors the products.

• WHY? Consider enthalpy and entropy.


• The elimination of water can be promoted under acidic or under basic conditions.

• Give a reasonable mechanism for each:



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• When a water is eliminated, two products are possible.

• Which will likely be the major product? Use the mechanism to explain.



• Because the aldol condensation is favored, often it is impossible to isolate the aldol product without elimination.


• Condensation is especially favored when extended conjugation results.


• At low temperatures, condensation is less favored, but the aldol product is still often difficult to isolate in good yield.




• Predict the major product of the following reaction. Be careful of stereochemistry.



• Substrates can react in a CROSSED aldol or MIXED aldolreaction. Predict the four possible products in the reaction below.


• Such a complicated mixture of products is not very synthetically practical. WHY?


• Practical CROSSED aldol reactions can be achieved through one of two methods:1. One of the substrates is relatively unhindered and without

alpha protons.



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1. One of the substrates is relatively unhindered and without alpha protons.



• Practical CROSSED aldol reactions can be achieved through one of two methods:2. One substrate is added dropwise to LDA forming the enolate

first. Subsequent addition of the second substrate produces the desired product.




• Describe a synthesis necessary to yield the following compound.



• Cyclic compounds can be formed through intramolecular aldol reactions.


• One group forms an enolate that attacks the other group.

• Recall that 5 and 6‐membered rings are most likely to form. WHY?

• Practice CONCEPTUAL CHECKPOINTs 22.25 through 22.27.


• Esters also undergo reversible condensations reactions.

22.4 Claisen Condensations

• Unlike a ketone or aldehyde, an ester has a leaving group.


• Esters also undergo reversible condensations reactions.


• The resulting doubly‐stabilized enolate must be treated with an acid in the last step. WHY?

• A beta‐ketoester is produced.Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e22-48

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• There are some limitations to the Claisen condensation:1. The starting ester must have two alpha protons because

removal of the second proton by the alkoxide ion is what drives the equilibrium forward.

2 Hydroxide cannot be used as the base to promote Claisen


2. Hydroxide cannot be used as the base to promote Claisen condensations because a hydrolysis reaction occurs between hydroxide and the ester.

3. An alkoxide equivalent to the –OR group of the ester is a good base because transesterification is avoided.



• Crossed Claisen reactions can also be achieved using the same strategies employed in crossed aldol reactions.


• Practice with CONCEPTUAL CHECKPOINT 22.30.


• Intramolecular Claisen condensations can also be achieved.


• This DIEKMANN CYCLIZATION proceeds through the expected 5‐membered ring transition state. DRAW it.



• Give reagents necessary to synthesize the following molecules.



O

OO

• The alpha position can be alkylated when an enolate is treated with an alkyl halide.

22.5 Alkylation of the Alpha Position

• The enolate attacks the alkyl halide via an SN2 reaction.


• When 2° or 3° alkyl halides are used, the enolate can act as a base in an E2 reaction. SHOW a mechanism.

• The aldol reaction also competes with the desired alkylation, so a strong base such as LDA must be used.


• Regioselectivity is often an issue when forming enolates.

• If the compound below is treated with a strong base, two enolates can form.


O

R

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• What is meant by kinetic and thermodynamic enolate?


22.5 Alkylation of the Alpha Position• For clarity, the kinetic and thermodynamic pathways are exaggerated below.

• Explain the energy differences below using steric and stability arguments.


• LDA is a strong base, and at low temperatures, it will react effectively in an irreversible manner.

• NaH is not quite as strong, and if heat is available, the system will be reversible.

• Practice with CONCEPTUAL CHECKPOINTs 22.33 and


22.24.


• Give necessary reagents to synthesize the compound below starting with carbon fragments with five carbons or less.



• The malonic ester synthesis allows a halide to be converted into a carboxylic acid with two additional carbons.


• Diethyl malonate is first treated with a base to form a doubly‐stabilized enolate.


• The enolate is treated with the alkyl halide.


• The resulting diester can be hydrolyzed with acid or base, and using heat.


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• One of the resulting carboxylic acid groups can be DECARBOXYLATED with heat through a pericyclic reaction.


• Why isn’t the second carboxylic acid group removed?


• Here is an example of the overall synthesis.



• Double alkylation can also be achieved:



• The acetoacetic ester synthesis is a very similar process.


• Give a complete mechanism for the process below.




• Recall that α,β‐unsaturated carbonyls can be made easily through aldol condensations.

22.6 Conjugate Addition Reactions

• α,β‐unsaturated carbonyls have three resonance contributors.

• Which contributors are electrophilic?Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e22-65

• Grignard reagents generally attack the carbonyl position of α,β‐unsaturated carbonyls yielding a 1,2 addition.


• In contrast, Gilman reagents generally attacks the beta position giving 1,4 addition, or CONJUGATE ADDITION.


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• Conjugate addition of α,β‐unsaturated carbonyls starts with attack at the beta position.


• WHY does the nucleophile generally favor attacking the beta position?


• More reactive nucleophiles (e.g. Grignard) are more likely to attack the carbonyl directly. WHY?

• Enolates are generally less reactive than Grignards but more reactive than Gilman reagents, so enolates often i i f 1 2 d 1 4 ddi i d


give a mixture of 1,2‐ and 1,4‐addition products.

• Doubly‐stabilized enolates are stable enough to react primarily at the beta position.


• When an enolate attacks a beta carbon, the process is called a Michael addition.



• Give a mechanism showing the reaction between the two compounds shown below.




• Because singly‐stabilized enolates do not give high yielding Michael additions, Gilbert Stork developed a synthesis using an enamine intermediate.

• Recall the enamine synthesis from Chapter 20.



• Enolates and enamines have reactivity in common.


• The enamine is less nucleophilic and more likely to act as a Michael donor.


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• Water hydrolyzes the imine, and tautomerizes and protonates the enol.


• Give reagents necessary to synthesize the molecule below using the Stork enamine synthesis .


O O



• The ROBINSON ANNULATION utilizes a Michael addition followed by an aldol condensation.




• Most of the reactions in this chapter are C–C bond forming.

• Three of the reactions yield a product with two functional groups.

22.7 Synthetic Strategies

• The positions of the functional groups in the product can be used to design necessary reagents in the synthesis.



• Stork enamine synthesis 1,5‐dicarbonyl compounds.


• Aldol and Claisen 1,3‐difunctional compounds.


• We have learned two methods of alkylation:1. The alpha position of an enolate attacks an alkyl halide.

2. A Michael donor attacks the beta position of a Michael acceptor.

Th t ti l b bi d


• These two reactions can also be combined:

• Give a reasonable mechanism.

• Practice with SKILLBUILDER 22.9.Copyright 2012 John Wiley & Sons, Inc. Klein, Organic Chemistry 1e22-78

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• Give reagents necessary for the following synthesis.


O O


O

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ch22 - Laney College4/25/2012 4 • When a proton is alpha to two different carbonyl groups, its...

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