enols and enolates - mitarea

Topic 9

Enols and Enolates

Introduction α Carbon Chemistry: Enols and Enolates

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

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

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

Introduction α Carbon Chemistry: Enols and Enolates

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

• The solvent can affect the exact percentages

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

Introduction α Carbon Chemistry: Enols and Enolates

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

Introduction α Carbon Chemistry: Enols and Enolates

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

Introduction α Carbon Chemistry: Enols and Enolates

• 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 carbon atom

Introduction α Carbon Chemistry: Enols and Enolates

• In the presence of a strong base, an enolate forms

Introduction α Carbon Chemistry: Enols and Enolates

• Enolates are called ambident nucleophiles (ambi is Latin for “both” and dent is Latin for “teeth”)

• The enolate can undergo C-attack or O-attack

• Enolates generally undergo C-attack.

Introduction α Carbon Chemistry: Enols and Enolates

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

Introduction α Carbon Chemistry: Enols and Enolates

• When pKa values are similar, both products and reactants are present in significant amounts

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

Introduction α Carbon Chemistry: Enols and Enolates

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

• 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?

Introduction α Carbon Chemistry: Enols and Enolates

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

Introduction α Carbon Chemistry: Enols and Enolates

Lithium diisopropylamide (LDA)Hexamethyldisilazanes [(CH3)3Si]2N-

(LiHMDS, KHMDS, NaHMDS)

Deprotonation by the conjugate base of a weak acid

Deprotonation by the conjugate base of an acid a comparable pKa

Irreversible deprotonation

Introduction α Carbon Chemistry: Enols and Enolates

For: Irreversible deprotonation

Identify the most acidic hydrogens in each of the following compounds

and indicate which of them will be deprotonated more than 99% by a

solution of sodium ethoxide in ethanol

Pentan-2-one

1-Phenylpropanone

Cyclohexan-1,3-dione

Write the structure of the possible

enolates

Indicates which of them will predominate

under conditions of (i) kinetic control and (ii)

thermodynamic control.

Write the structure of the most stable

tautomer of each of the following

compounds:

Which ketone, 1,2-diphenylethanone, or 1,3-diphenylpropan-3-one

will have the highest amount of enol at equilibrium?

Pentan-2,4-dione

15% enol

92%

enol

Water

Hexane

• Acid-catalyzed α-halogenation

α Halogenation of Enols and Enolates

• 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

α Halogenation of Enols and Enolates

• The Hell-Volhard Zelinski reaction brominates the alpha carbon of a carboxylic acid

α Halogenation of Enols and Enolates

• α halogenation can also be achieved under basic conditions

α Halogenation of Enols and Enolates

• The base abstracts a proton to form the enolate, which then functions as a nucleophile and undergoes α halogenation.

• After the first halogenation reaction occurs, the presence of the halogen renders the α position more acidic, and the second halogenation step occurs more rapidly.

• As a result, it is often difficult to isolate the monobrominatedproduct.

• Haloform test for methyl ketones

• 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

α Halogenation of Enols and Enolates

The reaction of 1 mol of Br2 with 1 mol of PhCOCH2CH3 in a basic media forms

0.5 mol of PhCOCBr2CH3 leaving 0.5 mol of PhCOCH2CH3 unreacted.

Reaction of 3-methylbutan-2-one with bromine under acidic conditions of a

mixture of two monobrominated derivatives in a 95: 5 ratio

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

• The enolate attacks the alkyl halide via an SN2 reaction

Alkylation of the α-Carbon

Alkylation of the α-Carbon

• 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

Alkylation of the α-Carbon

• 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

Alkylation of the α-Carbon: Malonic Synthesis

Alkylation of the α-Carbon: Malonic Synthesis

• Example of the overall synthesis

Alkylation of the α-Carbon: Malonic Synthesis

• Double alkylation:

• Practice with SkillBuilder 22.5

Alkylation of the α-Carbon: Malonic Synthesis

Identifies the product that is formed when the conjugate base of diethyl

malonate reacts with each of the following electrophiles followed by

standard workup with diluted acid

IUPAC Nomenclature

Barbituric acid: Pyrimidine-2,4,6(1H,3H,5H)-trione

Thiobarbituric acid: 2-Thioxodihydropyrimidine-4,6(1H,5H)-dione

Barbituric and Thiobarbituric Acids• Barbituric acid derivatives can be utilized as a sedative–hypnotic,

anesthetic, and anticonvulsant

• Synthesis from malonic acid

Barbituric and Thiobarbituric Acids

lactim dilactim trilactim

Tautamericequilibirum

• The acetoacetic ester synthesis is a very similar process

Alkylation of the α-Carbon: The Acetoacetic Ester synthesis

Why it is not possible to synthesize the following ketones from the acetoacetic

esters:

(a) Methyl tert-butyl ketone

(b) Benzyl methyl ketone

(c) 4,4-Dimethylpentan-2-one

High nucleophilicity at the β carbon

ENAMINES

Alkylation and Acylation of the α-Carbon via Enamines

IMINES Grignard reagentsLithium amides

IMINE ANIONMore nucleophilic tan enolates

Alkylation of Aldehydes via Imine Anions

Direct alkylation of aldehydes is not possible due to the competition with the aldol addition reaction (see next slides)

• 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 occurs

• The product features both aldehyde and alcohol groups

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

Aldol Reactions

Aldol Reactions• The aldol mechanism

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

Aldol Reactions

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

• Mechanism for the retro-aldol reaction?

Aldol Reactions

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

Aldol Reactions

The process is called an aldol

condensation, because water is given off

The elimination reaction above is an

equilibrium, which generally favors the

products

The driving force for is

formation of a conjugated

system.

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

• Normally, alcohols do not undergo dehydration in the presence of a strong base

• But here, the presence of the carbonyl group enables the dehydration reaction to occur.

Aldol Reactions

• Normally, alcohols do not undergo dehydration in the presence of a strong base

• But here, the presence of the carbonyl group enables the dehydration reaction to occur.

• The α position is first deprotonated to form an enolate ion, followed by expulsion of a hydroxide ion to produce α,β unsaturation.

• This two-step process, which is different from the elimination mechanism that you saw (E2) , is called an E1cb mechanism.

• In an E1cb mechanism, the leaving group only leaves after deprotonation occurs.

Aldol Condesation

Aldol Condensation: Mechanism

• When a water is eliminated, two products are possible

Aldol Reactions

• The reaction conditions required for an aldol condensation are only slightly more vigorous than the conditions required for an aldol addition reaction.

• In some cases, it is not even possible to isolate the β-hydroxyketone.

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

Aldol Reactions

• Substrates can react in a crossed aldol or mixed aldol reaction.

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

Aldol Reactions

• Practical crossed aldol reactions can be achieved through two methods1. Method 1: the substrates is relatively unhindered and without alpha

protons

Aldol Reactions

Claisen-Schmidt Condensation

2. Method 2: Forming an enolate first (using i. e. LDA), and subsequent addition of the second substrate produces the desired product

Aldol Reactions

• Cyclic compounds can be formed through intramolecular aldol reactions

Intramolecular Aldol Reactions/Condensations

• One group forms an enolate that attacks the other group

• 5 and 6-membered rings are most likely to form.

Write the aldol condensation product obtained when 2-acetylfuran is heated in the

presence of a base.

Identify the reagents needed to prepare the following compound by aldol

condensation

Nitro Aldol Reaction/Condensation: Henry Reaction

Nitro Aldol Reaction/Condensation: Henry Reaction

Nef Reaction

½ N2O + 3/2 H2O

Henry - Nef Reaction

Claisen Condensations

β-ketoesters

Unlike a ketone or aldehyde,

an ester has a leaving group

Reversible condensations reaction

The resulting doubly-stabilized enolate

must be treated with an acid in a last step.

2) H3O+

Claisen CondensationsThe starting ester must have 2 α

protons, because removal of the

second proton by the alkoxide

ion is what drives the equilibrium

forward

Hydroxide cannot be used as the base to promote

Claisen condensations, because a hydrolysis reaction

occurs between hydroxide and the ester

An alkoxide equivalent to the

–OR group of the ester is a

good base, because

transesterification is avoided

2) H3O+

A subsequent step

Write a mechanism

Cross Claisen Condensations

Intramolecular Claisen Condensations: Dieckeman Cyclization

Acylation of Ketones

Deduce the products that will be obtained in each of the following

transformations. Write a reasonable mechanism

Mannich Reaction

Mannich Base

Mechanism

Synthesis of enonesHOFFMANN ELIMINATION

EXAMPLES OF APPLICATION OF THE MANNICH REACTION IN SYNTHESIS

SYNTHESIS OF DRUGS (ARYLALKYLAMINE SYSTEMS)

Muscarinic antagonist

analgesic

cycrimine

tolpropamine

[(2S,3R)-4-(dimethylamino)-3-

methyl-1,2-diphenylbutan-2-yl]

propanoate

dextropropoxyphene

antihistamine

• α,β-unsaturated carbonyls have three resonance contributors

Conjugate Addition Reactions

Electrophilic centers

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

• In contrast, Gilman reagents generally attacks the βposition giving 1,4 addition or conjugate addition

Conjugate Addition Reactions

• Kinetic control• More likely with

aldehydes and acid chlorides

• Strong nucleophile

Reactivity of Carbonyl Compounds α,β-Unsaturated

• Thermodynamiccontrol

• More likely withketones and esters

• Weak nucleophileWhen the nucleophiles is a stabilized carbanion, attacks a β carbon, the process is called a Michael addition

More reactive

nucleophiles (e.g.,

Grignard) are more

likely to attack the

carbonyl directly

Reactivity of Carbonyl Compounds α,β-Unsaturated

Enolates are generally

less reactive than

Grignards but more

reactive than Gilman

reagents, so enolates

often give a mixture of

1,2- and 1,4- addition

productsWhen the nucleophiles is a stabilized carbanion, attacks a β carbon, the process is called a Michael addition

Doubly-stabilized

enolates are stable

enough to react

primarily at the beta

position

Conjugate Addition Reactions

Reactivity of Carbonyl Compounds α,β-Unsaturated

Conjugate Addition Reactions

C≡N- RS- R2NH

Michael Addition

• Enolates and enamines have reactivity in common

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

Conjugate Addition Reactions: Stork Reaction

• Water hydrolyzes the imine and tautomerizes and protonates the enol

Conjugate Addition Reactions: Stork Reaction

• The Robinson Annulation utilizes the Michael addition followed by an aldol condensation

Conjugate Addition Reactions

Write a

mechanism

Give the structure of A, B and

C