enols and enolates - mitarea
TRANSCRIPT
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