*3 enolates and alkylations aldol - claisen - michael

1!

1) Keto-Enol Tautomerism A) acid catalyzed

Keto form

Enol form

(more stable)

(less stable)

There MUST be a hydrogen on the α-carbon

(only need a tiny amount)

2!

B) base catalyzed

Keto form

Enol form

(more stable)

(less stable)

2) Keto-Enol Tautomerism There MUST be a hydrogen on the α-carbon

(only need a tiny amount)

A) INTRAmolecular hydrogen bonding

B) Aromaticity

3) What Stabilizes the Enol Tautomer ?

(has conjugation)

(has aromaticity)

Chapter 22! 4!

50% (S) Enantiomer

50% (R) Enantiomer 4) Keto-Enol Tautomerization: Racemization

Racemic Mixture 50:50 mix

of each enantiomer

(S) Enantiomer only

1) An Enol is a weak Nucleophile

Carbonyl compounds that have an α-hydrogen(s) will form an enol, which will undergo substitution reactions at the α-carbon:

an α-substitution reaction

2A) Enol Reaction: Acid-Catalyzed α-Halogenation

2

The dipole δ+/δ- that forms in the new carbon-halogen bond

destabilizes the a-carbon towards tautomerization

(forming another enol and reacting further).

Mechanism

Only ONE halogenation

Acetic acid commonly serves as the acid catalyst. (and the solvent)

2B) Enol Reaction: Acid-Catalyzed α-Halogenation

4!

3A) Hell-Volhardt-Zelinsky Reaction (HVZ) overall reaction

P + Br2 → PBr3 How to make PBr3

5!

3B) Hell-Volhardt-Zelinsky Reaction Mechanism

1)

2)

2)

2)

α-halo carboxylic acid derivatives undergo E2 reactions by heating in the presence of pyridine

Enone

4) Follow-On Reaction of α-halo carbonyls α-halo ketones undergo E2 reactions

by heating in the presence of t-butoxide (KO-tBu))

Enone

Enone

HVZ product

HVZ product

The α-Hydrogen Is Slightly Acidic

the anion is stabilized by resonance

The partial positive charge on the carbonyl carbon helps stabilize the negative charge forming on the adjacent carbon.

So, hydrogens on carbons next to ANY EWG are slightly acidic.

Examples

Enolate Equilibrium: Example #1

Enolate Equilibrium: Example #2

Enolate Equilibrium: Example #3

Enolates of Unsymmetrical Ketones when treated with base, two enolates are possible.

•  Path [1] occurs faster (Kinetic Control at Low Temp.) because it results in removal of the less hindered 20 H but forms the less stable enolate.

•  Path [2] results in formation of the more stable enolate (under Thermodynamic Control at higher temperature) when equilibrium is established.

2

•  Very Strong (nonnucleophilic) Base ensures that the easiest to form enolate is produced rapidly. A bulky base like LDA removes the more accessible α-proton on the less substituted carbon much faster than an α-proton from the more sterically hindered side..

•  Polar Aprotic solvent: polar to dissolve the polar starting materials and intermediates and aprotic so that it does not protonate the less stable enolate that is formed first.

•  Low temperature (-78°C) to prevent the kinetic enolate from equilibrating to the more stable thermodynamic enolate.

Kineticic Enolate (from unsymmetrical ketones) is favored by:

3

Thermodynamic Enolate (from unsymmetrical ketones) is favored by:

•  Strong Base that can form all enolates, so that the more stable, more substituted enolate is present in a higher concentration. Common bases are Na+¯OCH2CH3, and other alkoxides.

•  Protic Solvent (CH3CH2OH and other alcohols). For the reaction to be reversible, enolates need to be protonated to re-form the carbonyl starting material.

•  Heat (25°C or higher). Enough energy is needed to establish equilibrium, so the more stable, more substituted enolate is present in a higher concentration.

4

Making (about 100%) Thermodynamic Enolate

and silyl halides (R3Si-X)

The Carbon site acts like a nucleophile (attacks carbons)

An Enolate is a Great Nucleophile/Base

The Oxygen site acts like a base (attacks protons)

Treatment of propiophenone with Br2 and aqueous hydroxide, ¯OH

yields a dibromoketone.

2A) Enolate Reactions: Base-Promoted Halogenation

2B) Enolate Reactions: Base-Promoted Halogenation

The mono-halogenated product has a more acidic α-hydrogen

than the a-hydrogen in the initial reactant.

Cannot stop the Halogenation Reaction (in base) after addition of just one halogen atom to the α carbon.

(not catalytic)

3A) Enolate Reactions: The Haloform Reaction

If I2 is used, haloform reaction yields iodoform

If Br2 is used, haloform reaction yields bromoform

If Cl2 is used, haloform reaction yields chloroform

An Iodoform reaction produces carboxylates (then are protonated with acid to carboxylic acids)

and iodoform (yellow color) from methyl ketone (reactants).

Iodoform Test for methyl ketones

3B) Enolate Reactions: The Haloform Reaction

HO- (xs) I2 (xs)

Treatment of an enolate with an alkyl halide results in alkylation substitute OUT H (Hydrogen) / substitute IN R (alkyl group) on the α carbon atom.

4A) Enolate Reactions: Direct Alkylation (with R-X)

4B) Enolate Reactions: Direct Alkylation (with R-X) This is an SN2 reaction, so extremely fast with methyl halides and fast with primary alkyl halides

(tertiary halides (R-X) do NOT work)

1

Enolate Alkylations:

The acetoacetic ester synthesis: •  is a stepwise method to make a methyl ketone

(having one or two alkyl groups on the α carbon). •  Uses the reactant ethyl acetoacetate

1) Acetoacetic Ester Synthesis (AES)

from double alkylation from single alkylation

2

1) Acetoacetic Ester Synthesis (AES)

A) Single Alkylation

3!

General Decarboxylation Mechanism

methyl

In AES (using ethyl acetoacetate), the decarboxylation step always forms a methyl ketone.

4

B) Double Alkylation 1) Acetoacetic Ester Synthesis (AES)

5!

B) Double Alkylation mechanism

Decarboxylation (loss of CO2)

1) Acetoacetic Ester Synthesis (AES)

1) 2)

4) 3)

6

Key: Both R-X (alkyl halides) are in the same reagent

C) INTRAmolecular AES (Ring Forming) 1) Acetoacetic Ester Synthesis (AES)

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to determine what starting materials are needed to prepare a given methyl ketone

using the acetoacetic ester synthesis (AES).

1) Acetoacetic Ester Synthesis (AES) D) Use Retro-Synthetic Analysis

1

Enolate Alkylations:

The malonic ester synthesis: •  is a stepwise method to make a carboxylic acid

(having one or two alkyl groups on the α carbon). •  Uses the reactant diethyl malonate

2) Malonic Ester Synthesis (MES)

from double alkylation from single alkylation

2) Malonic Ester Synthesis (MES)

A) Single Alkylation

example

1) The diester with acid, water, heeeet will hydrolyzes both esters to carboxy groups.

2) β-Diacids are unstable to heat and will decarboxylate resulting in a carboxylic acid and CO2(gas).

General Decarboxylation Mechanism

Overall

4

2) Malonic Ester Synthesis (MES) B) Double Alkylation

5

C) INTRAmolecular MES (Ring Forming) 2) Malonic Ester Synthesis (MES)

Key: Both R-X (alkyl halides) are in the same reagent

6

D) Use Retro-Synthetic Analysis 2) Malonic Ester Synthesis (MES)

to determine what starting materials are needed to prepare a given carboxylic acid

using the malonic ester synthesis (MES).

The Aldol Reaction A) Self-Condensation Reaction

The Aldol Reaction A) Self-Condensation Reaction

One molecule of a carbonyl compound acts as a nucleophile and

the other carbonyl compound acts as an electrophile

The Aldol Addition product is often not isolated.

Instead, it loses water (H2O) from the α and β carbons to form a Aldol Condensation product (an enone).

Aldol Addition Product Aldol Condensation Product

The Aldol Reaction

Heat Acid or Base

(dehydration)

Enone

The Aldol Addition -vs- Condensation Products

The Aldol Reaction The Aldol Addition -vs- Condensation Products

Examples of Aldol Addition products

Draw the Aldol Condensation

Products

Conjugated Enones

The Aldol Reaction B) Mixed/Crossed - Directed (Stepwise)

1) 2)

3)

Take Note: How much enolate (what percent) is formed?

The Aldol Reaction B) Mixed/Crossed - Directed (Stepwise) Take Note: How much enolate (what percent) is formed?

1) 2)

3)

Acid + heat (or Base + Heat) will form the Aldol Condensation Product Draw the structure of the

Aldol Condensation product

The Aldol Reaction C) Mixed/Crossed – Claisen-Schmidt Take Note: The electrophile (aldehyde or ketone) has NO α-Hydrogens Take Note: The electrophile is in situ

enone

The Aldol Reaction C) Mixed/Crossed – Claisen-Schmidt Take Note: The electrophile (aldehyde or ketone) has NO α-Hydrogens Take Note: The electrophile is in situ

Slower Faster

Relative Rates of Enolate Reactions

Major Addition Product

We will learn the

The Aldol Reaction D) Mixed/Crossed - Directed (in situ) Take Note: Electrophile is in situ Take Note: The enolate is very easily formed (compared to the electrophile)

The Aldol Reaction D) Mixed/Crossed - Directed (in situ) Take Note: Electrophile is in situ

What is the weakest base that you can use and still product 100% enolate?

Draw the structure of the Enolate from each

Take Note: The enolate is very easily formed (compared to the electrophile)

active methylene compounds are more reactive towards base

The Aldol Reaction E) INTRAmolecular Take Note: Electrophile is within the same molecule Take Note: only form unstrained 5- or 6-membered rings

A mixture of products may form from unsymmetrical reactants

The Aldol Reaction E) INTRAmolecular Take Note: Electrophile is within the same molecule Take Note: only form unstrained 5- or 6-membered rings

A mixture of products may form from unsymmetrical reactants

Draw the structure of the OTHER cyclopentenone that forms?

The Aldol Reaction F) RetroSynthetic Analysis

The Aldol Reaction F) Retro Synthetic Analysis

Draw the reagents structures needed to make each product shown

Which Aldol Reaction Type (Self / Directed(stepwise) / Directed(in situ) / Claisen-Schmidt / INTRAmolecular)

was needed to make each product shown ?

The Claisen Reaction: Any enolate attacking an ester

The product will be a 1,3-dicarbonyl compound

1)

2)

Must have at least two α-hydrogens

on the reactant.

two molecules of an ester react (one as the enolate / one as the carbonyl electrophile)

in the presence of an alkoxide (RO-) base to form a 1,3-dicarbonyl compound (β-keto ester).

A) The Claisen Reaction: The Self Claisen

The product will be a 1,3-dicarbonyl compound

A Claisen reaction between two different carbonyl compounds is called a mixed/crossed Claisen reaction.

Only one enolate can form (because only one has α hydrogens)

B1) The Claisen Reaction: The Mixed/Crossed Claisen

The product will be a 1,3-dicarbonyl compound

Special Case #1

A Claisen reaction between two different carbonyl compounds is called a mixed/crossed Claisen reaction.

Only one enolate forms (because it has more acidic α hydrogens)

B2) The Claisen Reaction: The Mixed/Crossed Claisen

The product will be a 1,3-dicarbonyl compound

Special Case #2

an enolate reacts with with ethyl chloroformate –or- diethyl carbonate.

B3) The Claisen Reaction: The Mixed/Crossed Claisen

The product will be a 1,3-dicarbonyl compound

The product will be a 1,3-dicarbonyl compound

an enolate reacts with with ethyl chloroformate -or- diethyl carbonate.

B4) The Claisen Reaction: The Mixed/Crossed Claisen

The product will be a 1,3-dicarbonyl compound

Mechanism

The Dieckmann Condensation C1) The INTRAmolecular Claisen Reaction:

Only form unstrained 5- or 6-membered rings

The product will be a 1,3-dicarbonyl compound

The product will be a 1,3-dicarbonyl compound

The Dieckmann Condensation C2) The INTRAmolecular Claisen Reaction:

Mechanism 1)

2)

symmetrical Dilute conditions (more solvent) favor INTRAmolecular reactions

The product will be a 1,3-dicarbonyl compound

D) The Claisen Reaction: Retro Synthetic Analysis Two different Claisen Condensations

can be used to make the same 1,3-dicarbonyl compound.

Direct Addition –vs- Conjugate Addition 1,4-addition 1,2-addition

Direct Addition –vs- Conjugate Addition 1,4-addition 1,2-addition

A1) The Michael Reaction: stepwise

The product will be a 1,5-dicarbonyl compound

Any enolate attacking an enone 1) the base deprotonates the carbonyl compound (with α-hydrogen); 2) the enone is added to the reaction flask; then 3) The resulting enolate is quenched with acid workup OR an alkyl halide

A2) The Michael Reaction: in situ Any enolate attacking an enone

where the base; carbonyl compound (with α-hydrogen); and enone

are ALL in the reaction flask at the same time

The product will be a 1,5-dicarbonyl compound enolate

2) Acid Workup

C2) The INTRAmolecular Michael Reaction:

Dilute conditions (more solvent) favor INTRAmolecular reactions

The product will be a 1,5-dicarbonyl compound

B) The Michael Reaction: Retro Synthetic Analysis Two different Michael Condensations

can be used to make the same 1,5-dicarbonyl compound.

The Robinson Annulation: Introduction

The Robinson Annulation combines

1) Michael reaction

2) Enolate Swap

3) INTRAmolecular Aldol reaction.

An annulation is a ring-forming reaction.

The product will be a cyclohexenone

You need an α,β-unsaturated carbonyl compound (enone) and an enolate.

To generate the enolate component of the Robinson annulation, ¯OH in H2O or ¯OEt in EtOH are typically used.

The Robinson Annulation: Examples

The product will be a cyclohexenone

The product will be a cyclohexenone

The Robinson Annulation: Mechanism