Chapter 22: The Chemistry of Enolate Ions, Enols, and α, β-Unsaturated Carbonyl Compounds

Ester → (more/less) acidic and (more/less) stable enolate ions than ketones.

less, less

Enolate formation from ketones and esters is favored in the presence of…

sterically hindered strong non-nucleophilic bases such as LDA

The N—H of primary and secondary amides is (more/less) acidic than the α-H on an α-carbon.

more

Order the acidic strength of these from strong to weak:
aldehydes, amides, carboxylic acids, esters, ketones

carboxylic acids > amides > aldehydes/ketones > esters

draw the mechanism for the exchange of α-H for D in basic conditions

What kinds of enolates are racemized by base?

enolates with asymmetric α-carbons

enol

any compound where a —OH group is on an α-carbon of a C=C

β-dicarbonyl compounds are more stable in the enol form due to…

intramolecular hydrogen bonding and resonance

draw the mechanism for base-catalyzed enolization

draw the mechanism for acid-catalyzed enolization

What is the reagent used for α-halogenation of ketones in acidic conditions?

X₂, CH₃COOH

What is the reagent used for α-halogenation of ketones in basic conditions?

X₂, NaOH

In α-halogenation of ketones in acidic conditions, only _____ occurs.

monohalogenation

show the mechanism for α-halogenation of ketones in acidic conditions

In α-halogenation of ketones in basic conditions, only _____ occurs.

polysubstitution

Why does polysubstitution result from α-halogenation of ketones in basic conditions?

increased reactivity of mono-bromo compounds towards the base

haloform reaction

when methyl ketone is used in base catalyzed α-halogenation of ketones, a carboxylic acid and haloform (HCX₃) are formed

draw what the enolate ion will look like on the final

draw the mechanism for the haloform reaction

What does the Hell-Volhard-Zelinsky (HVZ) reaction do?

α-bromination of carboxylic acids

What reagent is used in the Hell-Volhard-Zelinsky (HVZ) reaction?

Br₂, P or PBr₃

What must the carboxylic acid have in order to do the Hell-Volhard-Zelinsky (HVZ) reaction?

an α-hydrogen

solve

Rates of SN2 rxn in α-halo carbonyl compounds are much (faster/slower) than alkyl halides.

faster

Do α-halo carbonyl compounds undergo SN1 rxns?

no

Do α-halo carbonyl compounds undergo SN2 rxns?

yes, very quickly

What happens in an aldol reaction?

an enol or enolate ion acts as a nucleophile and adds to the carbonyl carbon of an aldehyde or ketone

draw the mechanism for base-catalyzed aldol addition reaction

Aldol reaction consists of ____ and ____.

addition, condensation

Aldol addition is (reversible/irreversible).

reversible

Equilibrium for aldol addition is more favorable for aldehydes or ketones?

aldehydes

What is aldol condensation?

aldol addition followed by elimination

What is the mechanism called for the elimination in aldol condensation?

E1cB (conj base)

draw the mechanism for base-catalyzed aldol condensation reaction

What do acid-catalyzed aldol reactions produce?

condensation products;

α,β-unsaturated aldehydes or ketones

draw the mechanism for acid-catalyzed aldol condensation reaction

Intramolecular aldol reactions result in _____ formation.

ring

Intramolecular aldol reactions are favorable for the formation of 5- and 6-membered rings due to…

proximity effect

Cross aldol reactions involve…

two different enolizable carbonyl compounds that produce a mixture of products

How many products can A and P give for a crossed aldol reaction?

4;

A + A’,
P + A’,
A + P’,
P + P’

Claisen-Schmidt condensation

crossed aldol condensation that uses reactants chosen to limit the number of possible products

How does the Claisen-Schmidt crossed aldol condensation limit the number of possible products?

by using a carbonyl compound with no α-hydrogens

What happens in a directed aldol reaction?

a strong base is used to generate the enolate of a carbonyl compound in a separate step;

the preformed enolate reacts with an aldehyde or ketone to make a crossed aldol product

What reagent is used in a directed aldol reaction?

LDA, THF
(-78ºC)

In directed aldol reaction, unsymmetrical ketones can form…

two different enolates, kinetic enolate B and thermodynamic enolate A

What does LDA do?

forms enolate ions rapidly and irreversibly from ketones at -78ºC

What enolate formation does LDA favor?

kinetic enolate formation

draw the mechanism for directed aldol reaction

What is a Claisen condensation and what does it do?

reaction between an ester enolate and an ester that forms a β-keto ester via nucleophilic acyl substitution

What is matched to the ester alkoxy group in a Claisen condensation to avoid transesterification?

alkoxide base and alcohol solvent

What is the reagent used in the Claisen condensation?

1. NaOEt (slightly more than 1 equivalent), EtOH

2. H₃O⁺ (workup)

Dieckmann condensation reaction

intramolecular version of the Claisen condensation reaction

draw the mechanism for the Claisen condensation mechanism

What is required for a Claisen condensation reaction?

2 α-hydrogens

Why is no product observed when no α-hydrogens are present in a Claisen condensation reaction?

the final deprotonation step would not be able to occur and equilibrium would favor the reactants → reverts the reaction to the starting materials

What is the difference between aldol condensation and Claisen condensation?

Aldol:
1. addition rxn of enolate w aldehyde/ketone + dehydration
2. catalyzed by both acid and base
3. aldol addition requires only 1 α-hydrogen

Claisen:
1. nucleophilic acyl substitution rxn of enolate w ester
2. requires full equivalent of base (not acid catalyzed)
3. requires 2 α-hydrogens

Crossed Claisen condensation reaction

Claisen condensation with two different esters

When is the crossed Claisen condensation reaction most useful?

if one ester is especially reactive or has no α-hydrogens

What is the product of this crossed Claisen condensation reaction of ketones with esters?

β-diketone

Alkylation of β-diesters leads to form…

a new C—C bond

How do you turn a malonic acid into carboxylic acids?

NaOH, H₂O

H₃O⁺
heat

draw the mechanism for forming a ketone from β-keto esters

solve

Reformatsky reaction

an enolate is formed by the reaction of powdered Zn with an α-bromo ester

Knoevenagel condensation reaction

aldol condensation reaction of malonic ester, acetoacetic ester, and a relatively acidic carbonyl compound

Alkenes that are conjugated with carbonyls are generally called…

α,β-unsaturated carbonyl compounds

Strongly basic nucleophiles (RLi, RMgX, LiAlH₄) react rapidly and irreversibly at the _____.

carbonyl carbon

Less basic nucleophiles (organocuprates, cyanide, enolates) react at the _____.

β-carbon (conjugate addition)

For α,β-unsaturated aldehydes and ketones, nucleophiles that undergo reversible carbonyl addition tend to favor…

conjugate addition

draw the mechanism for addition of HCN to an α,β carbonyl compound

solve conjugate addition with α,β-unsaturated esters

solve conjugate addition with α,β-unsaturated nitriles

draw the mechanism of acid-catalyzed conjugate addition to α,β carbonyl compounds

Michael additions

conjugate additions of stabilized enolates to α,β-unsaturated carbonyl compounds

What are Michael additions common for?

enolate ions derived from malonic ester derivatives and β-keto esters

solve

Robinson annulation

Michael addition followed by an intramolecular aldol condensation to form a 6-membered ring;

often yields cyclohexanone derivatives

solve using Robinson annulation

solve

Carbonyl reduction is (faster/slower) than conjugate addition and is (reversible/irreversible).

faster, irreversible

Reduction of α,β-unsaturated carbonyls occurs under (thermodynamic/kinetic) control.

kinetic

What reagent can reduce α,β-unsaturated ketones?

NaBH₄, MeOH

The C=C of α,β-unsaturated carbonyls can be selectively reduced by…

catalytic hydrogenation

Organolithium reagents (RLi) and Grignard reagents (RMgX) react with α,β-unsaturated carbonyl compounds at the…

carbonyl carbon

What do lithium dialkylcuprates (R₂CuLi) do to α,β-unsaturated carbonyl compounds?

they undergo conjugate addition and introduce an alkyl group at the β-carbon and retaining the carbonyl group in the product

solve

solve

draw the mechanism for addition of lithium dialkylcuprate reagents to this structure