Ch 22 Flashcards by Joshua Bunting

What is an enolate ion?

the conjugate base anion of a carbonyl compound formed when an alpha hydrogen is removed

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Enolate ions can act as (electrophiles/nucleophiles)

nucleophiles, because they are anions.

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What is an enol?

any compound when a hydroxide group is on one of the carbons in a double bond. (vinylic alcohol)

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The enol form and original carbonyl compound are considered ______ ______.

constitutional isomers.

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What is an alpha,beta unsaturated carbonyl compound?

Where there exists a double bond on the carbonyl compound connecting the alpha and beta carbon.

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The higher the pKa, the (more/less) acidic.

The higher the pKa, the less acidic

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Give 3 reasons for the acidity of alpha hydrogens

1) resonance stability and electron delocalization in the enolate ion
2) negative charge added to oxygen, an electronegative atom.
3) The polar dipole of the carbonyl can stabilize the carboxylate anion.

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Aldehydes and Ketones are (more/less) acidic than esters. And by approx how many pKa units?

Aldehydes and Ketones are about 7 pKa units more acidic than esters.

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Why are esters less acidic than Aldehydes and Ketones?

Esters do not have resonance when they are ionized, so it is more stable for them not to deprotonate.

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Nitrogen analogs of enolate ions

amides!

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Oxygen analogs of enolate ions

carboxylic acids!

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What is the rank of acidity of amides, aldehydes/ketones, and carboxylic acids?

Carboxylic acids>amides>(aldehydes/ketones)

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Enolate Ions can react with bronsted ____s.

bronsted acids

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Two consequences of enolate ion formation and protonation

1) replacement of H with D

2) racemization of chiral aldehydes and ketones

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Why are chiral aldehydes and ketones racemized?

the enolate ion is achiral and protonation from the bronsted acid can occur on either face.

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Enolate ions are also Lewis ___.

Lewis bases, and therefore nucleophiles.

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Enolate ions as nucleophiles often react with___(3)___

carbonyl carbons, alkyl halides, and sulfonate esters.

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What is a tautomer?

Constitutional isomers that undergo such rapid interconversions that you cannot separate them.

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How do tautomers relate to this chemistry?

A carbonyl compound and its enol are considered tautomers.

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Which are more stable: Enols or the carboxylic acid?

The carboxylic acid

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Why are carboxylic acids more stable than their enol counterparts?

The C=O bond is stronger in a carboxylic acid than the C=C bond. Also carbonyl oxygen provides some stabilization resonance.

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What is an instance where the enol is more stable than it’s carboxylic counterpart?

In aromatic rings, the enol (phenol) is more stable than the keto isomer because the keto breaks aromaticity.

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What is another example of a stable enol, and why?

Beta dicarbonyl compounds in their enol form have increased hydrogen bonding.

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Base catalyzed enolization: involves the intermediacy of ____

an enolate ion.

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Base catalyzed enolization: the ____ is the conjugate base of both the carbonyl compound and the enol.

enolate ion

Acid catalyzed enolization: An enol and its carbonyl isomer have the same ____

conjugate acid.

Acidity of Carbonyls: Rank allylic, amide, amine, ketone, aldehyde, ester, carboxylic acid

Most acidic= carboxylic acid>aldehyde>amide>ketone>ester>amine

Alpha Acidic Halogenation: 2 steps, and rates

First step: rate limiting formation of enol | Second step: fast halogenation step

Alpha Acidic Halogenation: Typically converts __ alpha hydrogens to halogens.

one

Base catalyzed Halogenation: Also called ____

The Haloform reaction

Base catalyzed Halogenation: typically replaces ____ alpha hydrogens with halogens

all

Base catalyzed Halogenation: The trihalomethane product is unstable and reacts with ____ and ____ to form a ____ and a ____.

OH and H3O+ to form a haloform and a carboxylic acid.

Hell-Volhard-Zelinsky Reaction Part I

Carboxylic acid + Br2 --red phosphorous or PBr3--> replaces an alpha hydrogen with Br.

Iodoform reaction

Alcohol --I2, base---> carbonyl

Hell Volhard Zelinsky Reaction Part II

acid bromide enol form adds another Br (from Br2) to become an alpha bromo acid bromide.

Hell Volhard Zelinsky Reaction Part III

in presence of small amount of PBr3, the alpha bromo acid bromide reacts with more carboxylic acid to form an alpha bromo acid.

Hell Volhard Zelinsky Reaction Overall ( 2 separate condition paths)

1) catalytic amount of PBr3: provides alpha bromo acid | 2) full equivalent of PBr3: provides an alpha bromo acid bromide

Alpha bromo acid bromide + alcohol=

alpha bromo ester.

Alpha halo carbonyl compounds with a good nucleophile (but weak base) provides a

alpha substituted carbonyl compound

Alpha halo carbonyl compounds undergo (SN2/SN1)

SN2, cannot undergo SN1

Why is SN1 not favored by carbonyl compounds?

The positive charge on the alpha carbon is destabilized ty the partial positive charge on the carbonyl carbon.

General Base catalyzed Aldol Reaction (aldol addition)

2 equivalents of aldehyde --(NaOH,H2O)--> aldol

What is an aldol?

A molecule with part alcohol, part aldehyde

General Base catalyzed Aldol Reaction Mechanism(3)

1) [nucleophile(enol form)] + aldehyde 2) Protonation 3) Addition product

Equilibrium for aldol addition is more favorable for (aldehydes/ketones)

more favorable for aldehydes than ketones

Aldol Condensation Rxn

an aldol addition product can undergo dehydration to afford an alpha, beta unsaturated aldehyde.

What favors an Aldol Condensation Step?

heat or excess base

What occurs during the condensation step (mechanism)

Base attacks an alpha hydrogen, which creates a double bond, as the OH leaves.

General Acid catalyzed Aldol Condensation

2 equivalents of aldehyde with the addition of acid provide an alpha, beta unsaturated carbonyl compound. THE ADDITION PRODUCT CANNOT BE ISOLATED.

What are crossed aldol reactions?

Different carbonyl compounds coming together in an aldol reaction.

Claisen-Schmidt Condensation

A ketone with alpha hydrogens condenses via --(NaOH)--> with an aldehyde with no alpha hydrogens, for example, benzaldehyde.

Intramolecular Aldol Condensation

can occur when more than one aldehyde or ketone group exists, for example can create 6 membered rings

Claisen Condensation

Base promoted condensation of two ester molecules to give a B keto ester

What is a B keto ester?

It is a ketone group B to an ester group.

Dieckmann condensation

an intramolecular Claisen condensation

Claisen Condensation: very similar to

saponification

Crossed Claisen Condensation

Combination of two different esters

Useful Crossed Claisen Condensations:

When one ester is particularly reactive, or has no alpha hydrogens.

Example of a useful crossed claisen condensation, and why:

ethyl formate: has no alpha hydrogens, and enhanced carbonyl reactivity ( easily interacts with nucleophiles.

Another control of Crossed Claisens

using one reagent in excess causes one to react preferentially.

Ketones and Esters (Claisen Condensation)

Ketone is more acidic and therefore forms the enolate. Ester cannot react with itself. Forms a B diketone.

What is a B diketone?

ketone on the beta position. Looks like a dicarbonyl.

Overall, Claisen condensations can be used in synthesis to create:

B dicarbonyl compounds, B keto esters, B diketones.

Retrosynthesis: Dicarbonyls with a carbon in between.

Cut the bond between central carbon and carbonyl carbon in both possible places, and place an HOEt there, putting the EtO on the piece with the carbonyl.

Aldol With LAH

Turns the carbonyl into an alcohol too.

Aldol with PCC

Turns the alcohol into a carbonyl too.

Alpha Beta unsaturated carbonyl compound with LAH

Turns the carbonyl into an alcohol.

Alpha Beta unsaturated carbonyl compound with H2/Pd

Removes the double bond

Alkylation of Ester Enolate Ions: Basic concept (general)

enolate ions can also acts as nucleophiles in SN2 Reactions

Malonic Ester Synthesis ( 4 steps)

Ionization, alkylation, saponification, decarboxylation

Direct Alkylation of Enolate Ions from Monoesters: Basic concept (general)

Alpha hydrogen replaced with alkyl component by e.g LDA in THF

What is LDA?

Lithium Diisopropyl Amide (a very strong non nucleophilic base that can esters to form their conjugate base ions)

Acetoacetic ester synthesis ( 3 steps)

saponification, protonation, decarboxylation

Conjugate Addition Reactions (General)

Places H-A across a double bond via enolate ion intermediate.

1,4 addn rxns (thermo/kinetic)

thermodynamic, adds the nucleophile to the 4 position on alkene

1,2 addn rxns (thermo/kinetic)

kinetic, adds the nucleophile to the carbonyl carbon.

Cu (cuprates) 1,4 addn, or 1,2?

1,4 thermodynamic product, soft

Li/Grignard 1,4 addn or 1,2?

1,2 kinetic, adds to the carbonyl carbon

Michael Addn

Diester + NaOEt creates enolate that adds to the 1,4 position of an alkene.