Aldehydes & Ketones Continued (Chapter 18) Flashcards
Tautomerization of Aldehydes/Ketones
The reversible conversion of an aldehyde/ketone to an enol via α-Hydrogen rearrangement and π-electron transfer.
Aldehyde/Ketone → Enol
Enol → Aldehyde/Ketone
Tautomerization
This reversible tautomerization process can occur in acidic conditions and basic conditions.
Aldehyde/Ketone → Enolate
Base-Catalyzed Deprotonation
Removal of the α-Hydrogen and subsequent π-electron transfer (C=O→C=C) yields the enolate ion.
Enol
A compound containing an alcohol group (—OH) adjacent to an alkene group (C=C).
One carbon atom of the alkene is bonded to the alcohol group subsituent.
Enolate
An anionic compoundcontaining an alkoxide group (—O–) adjacent to an alkene group (C=C).
One carbon atom of the alkene is bonded to the alkoxide group subsituent.
How is the α-Hydrogen deprotonation of an aldehyde/ketone possible?
The α-Hydrogen is highly acidic (i.e. pKa = 16–21)
Resonance stabilization of the deprotonated aldehyde/ketone compound (i.e. an enolate ion) promotes the dissocation of the C—Hα bond.
Reagents: Base-Catalyzed Deprotonation of α-Hydrogen
LDA
Lithium Diisopropylamide
α-Hydrogen Deprotonation: Kinetic Control vs. Thermodynamic Control
- Kinetic Control: At low temperatures, the base deprotonates the Iess hindered/substituted α-Hydrogen (to form the less stable enolate ion).
- Thermodynamic Control: At room/high temperatures, the base deprotonates the more hindered/substituted α-Hydrogen (to form the more stable enolate ion).
While the base is still more likely to initially depronate the less hindered/substituted α-Hydrogen at room/high temperatures (i.e. thermodynamic control), the reversibility of the deprotonation leads to the more stable enolate ion being the predominant product.
Characteristics: Kinetic Control
- Low Temperatures
- Short Reaction Times
- Unreversible
The less stable product isomer is the major product.
Characteristics: Thermodynamic Control
- Room/High Temperatures
- Long Reaction Times
- Reversible
The more stable product isomer is the major product.
Stability: Aldehye/Ketone vs. Enol
An enol is the less stable isomer of an aldehyde/ketone.
In the presence of acid or base, the enol will tauteromize to the more stable aldehyde/ketone isomer.
Methods for Ketone Synthesis
2°/3° Enol Tautomerization
Methods for Aldehyde Synthesis
0°/1° Enol Tautomerization
Alkyne → Ketone
Hg(II)-Catalyzed Hydration
An enol intermediate is formed (but NOT observed) following alcohol-addition and prior to ketone-yielding tautomerization.
Terminal Alkyne → Aldehyde
Hydroboration Oxidation
An enol intermediate is formed (but NOT observed) following alcohol-addition and prior to aldehyde-yielding tautomerization.
Reagents: Hg(II)-Catalyzed Alkyne Hydration
HgSO4, H2O, H2SO4
Reagents: Hydroboration-Oxidation Alkyne Hydration
- BH3
- H2O2, NaOH
Mechanism: Base-Catalyzed Aldehyde/Ketone Tautomerization
Base-Catalyzed Enolization
- Deprotonation of the α-Hydrogen (and subsequent π-electron transfer) to yield the Enolate ion.
- Protonation of the aldehydic/ketonic Oxygen to yield the Enol.
Product = Enol
Mechanism: Acid-Catalyzed Aldehyde/Ketone Tautomerization
Acid-Catalyzed Enolization
- Protonation of the aldehydic/ketonic Oxygen to yield the oxocarbenium ion.
- Deprotonation of the α-Hydrogen (and subsequent π-electron transfer) to yield the Enol.
Product = Enol
Mechanism: Base-Catalyzed Enol Tautomerization
- Deprotonation of the enolic alcohol group (—OH) to yield the enolate ion.
- π-electron rearrangement to yield the anionic α-Carbon aldehyde/ketone.
- Protonation of anionic α-Carbon to yield the (nonionic) aldehyde/ketone.
Product = Aldehyde/Ketone
Mechanism: Acid-Catalyzed Enol Tautomerization
- Protonation of the enolic alkene group (at the α-Carbon) AND transfer of π-electrons from Oxygen lone pair to Carbon-Oxygen bond (C=O) to yield the oxocarbenium ion.
- Depronation of oxocarbenium Oxygen yield the (nonionic) aldehyde/ketone.
Product = Aldehyde/Ketone
Deuterium Exchange of α-Hydrogens
All α-Hydrogens of an aldehyde/ketone are replaced with Deuterium isotopes.
The acidic α-Hydrogens are the ONLY hydrogen atoms replaced with Deuterium isotopes.
Reagents: Deuterium Exchange
D2O (Excess), OD–
Aldehyde/Ketone → Racemic Mixture
Isomerization of Aldehydic/Ketonic α-Stereoisomer
The isomerization reaction yields (1) the* reagent α-Isomer* and (2) its α-Stereoisomer.
Reagents: Isomerization α-Stereoisomer
CH3CH2O–, CH3CH2OH
Aldehyde/Ketone → α-Halogenated Aldehyde/Ketone
Electrophilic α-Halogenation
This α-halogenation reaction can occur in acidic conditions and basic conditions.
Reagents: Acid-Catalyzed α-Halogenation
X2, CH3CO2H, H2O (Solvent)
Electrophile = X2
Acid Catalyst = CH3CO2H
Reagents: Base-Catalyzed α-Halogenation
X2, NaOH, H2O (Solvent)
Electrophile = X2
Acid Catalyst = NaOH
Why do enols react faster with electrophiles than simple alkenes?
The alkene group of enols is more electron-rich than that of simple alkenes.
Since the alcohol substituent of the enol is electron-donating, the adjacent alkene group (i.e. α-Carbon) possesses a greater electron density (than a simple alkene).
Why do enolates react faster with electrophiles than simple alkenes?
The alkenyl α-Carbon of enols is more electron-rich than that of simple alkenes.
The enolate possesses an anionic α-Carbon resonance form, so the alkenyl α-Carbon possesses a greater electron density (than it would on a simple alkene).
Enolization Reactions: Acid-Catalyzed vs. Base-Catalyzed
Tautomerization
- Acid-Catalyzed: Protonation of the aldehydic/ketonic Oxygen (to form an oxocarbenium ion) occurs first.
- Base-Catalyzed: Deprotonation of the α-Hydrogen (to form an enolate ion) occurs first.
Carbonylization Reactions: Acid-Catalyzed vs. Base-Catalyzed
Tautomerization
- Acid-Catalyzed: Protonation of the α-Hydrogen (to form an oxocarbenium ion) occurs first.
- Base-Catalyzed: Deprotonation of the aldehydic/ketonic Oxygen (to form an enolate ion) occurs first.
What conditions will cause the tautomerization of enols
Enols will tautomerize in the presence of acid or base.
A minor amount of acid or base is sufficient to catalyze the transformation from the less-stable enol to the more-stable ketone/aldehyde.
Products of α-Halogenation: Acid-Catalyzed vs. Base Catalyzed
α-Halogenation of Aldehyde/Ketone
- Acid-Catalyzed: Monohalogenated Product
- Base-Catalyzed: Trihalogenated/Polyhalogenated Product
Under basic conditions, the α-Halogenation of aldehydes/ketones CANNOT be stopped at the monohalogenated stage.
Why is it NOT possible to stop base-catalyzed a-Halogenation at the monohalogenated stage?
α-Halogenation of Aldehydes/Ketones
The C—Hα bonds of the monohalogenated product are weaker (i.e. the α-Hydrogens are more acidic) than the C—Hα bonds of the starting material (due to the electron-withdrawing effect of the halogen).
The monohalogenated product will react faster with the halogen electrophile (X2) than the starting material did. (Each further-halogenated stage will react increasingly faster with the halogen electrophile to eventually halogenate all C—Hα bonds.)
Why is it possible to achieved the monohalogenated α-Halogenation product?
α-Halogenation of Aldehydes/Ketones
The alkenyl group of the tautomerized monohalogenated product is less electron-dense (i.e. less reactive) than the alkenyl group of the tautomerized starting material (due to the electron-withdrawing effect of the halogen).
The alkenyl group of the tautomerized monohalogenated product will attack the halogen electrophile (X2) slower than the alkenyl group of the starting material did.
Reagents: Carbonyl α-Alkylation
α-Alkylation of Aldehydes/Ketones
- LDA
- R—X
Aldehyde/Ketone → α-Alkylated Aldehyde/Ketone
Enamine α-Alkylation
Enamine α-Alkylation does NOT result in poly-α-alkylation and can be used to α-alkylate aldehydes AND ketones.
(Carbonyl α-Alkylation is rarely useful/practical for the synthesis of α-alkylated products.)
Reagents: Enamine α-Alkylation
α-Alkylation of Aldehydes/Ketones
- 2° Amine
- R—X
- H2O
Why is Carbonyl α-Alkylation is rarely useful/practical for the synthesis of α-alkylated products?
Many competing side reactions can potentially occur (e.g. E2 Elimination, Poly-α-Alkylation; Aldehyde Condensation) when the carbonyl α-Alkylation reagents are combined.
A more practical/useful alternative to carbonyl α-Alkation is enamine α-Alkylation.
α,β-Unsaturated Carbonyl Compound
- α,β-Unsaturated Aldehyde: A planar compound containing an aldehyde group in conjugation with an alkenyl group.
- α,β-Unsaturated Ketone: A planar compound containing a ketone group in conjugation with an alkenyl group.
The π-electrons of the carbon-oxygen double bond (C=O) are in conjugation with the π-electrons of the adjacent carbon-carbon double bond (C=C).
2 Aldehyde → α,β-Unsaturated Aldehyde
Di-α-Hydrogen Aldehydes OR Tri-α-Hydrogen Aldehydes
Aldol Condensation
- A trans carbon-carbon double bond (C=C) is formed between one aldehyde’s α-carbon and the other aldehyde’s carbonyl carbon.
Reagents: Aldol Condensation
Starting Material: 2 Aldehyde (Identical)
NaOH, Heat (Δ)
Aldol
A compound containing an aldehyde group and an alcohol group (—OH) on the β–carbon.
What is the driving force for the dehydration step of Aldol Condensation?
The formation of the π-conjugated system within the α,β-unsaturated aldehyde.
The charge delocalization of the π-conjugated system confers great stability to the unsaturated aldehyde product.
2 Aldehyde → Aldol
Mono-α-Hydrogen Aldehydes
Aldol Condensation
2 Aldehyde → Aldol = Intramolecular
Why are aldehydes containing zero α-hydrogens unable to undergo Aldol Condensation?
The aldehyde cannot be deprotonated at the α-position to yield an enolate.
Why are intermolecular Aldol Condensation reactions with ketone reagents thermodynamically unfavorable?
The carbonyl carbon of the ketone is stabilized via hyperconjugation from adjacent alkyl groups, so it is less electron-deficient and less prone to nucleophilic attack.
Why do intramolecular Aldol Condensation reactions occur faster than intermolecular reactions?
The intramolecular Aldol Condensation reaction exhibits favorable entropic effects (i.e. the starting reagent forms the α,β-unsaturated aldehyde and H2O).
Why are intermolecular Aldol Condensation reactions with ketone reagents possible?
The intramolecular Aldol Condensation reaction exhibits favorable entropic effects (i.e. the starting reagent forms the α,β-unsaturated aldehyde and H2O).
The positive entropic effects of the condensation reaction override its negative thermodynamic effects.
Synthesis Mechanisms: α,β-Unsaturated Aldehyde
- Aldol Condensation
- Allylic Alcohol Oxidation
α,β-Unsaturated Carbonyls as Simple Alkenes
An α,β-unsaturated aldehyde/ketone will react as a simple alkene if NONE of the other reagents are nucleophiles.
The alkenyl group of the α,β-unsaturated aldehyde/ketone is NOT involved in the reaction.
Reactions: α,β-Unsaturated Carbonyls as Simple Alkenes
- Metal-Catalyzed Hydrogenation of Alkene
- Electrophilic Halogenation of Alkene
- Diels-Alder Reaction
α,β-Unsaturated Carbonyls as Simple Aldehydes/Ketones
1,2-Addition
An α,β-unsaturated aldehyde/ketone will react as a simple aldehyde/ketone if it reacts with any nucleophilic organometallic, metal-hydride, hydroxylamine, or hydrazine compound.
The nucleophilic compound attacks the α,β-unsaturated aldehyde/ketone at the carbonyl carbon (and does NOT interact with the alkenyl group).
Reactions: α,β-Unsaturated Carbonyls as Simple Aldehydes/Ketones
- Grignard Reactions
- Organolithium Reactions
- Metal-Hydride Reduction
- Nucleophilic Hydroxylamine Addition
- Nucleophilic Hydrazine Addition
Hydroxylamine
NH2OH
1,2–Addition
Addition to α,β-Unsaturated Carbonyl
The α,β-unsaturated carbonyl acts as a simple aldehyde/ketone.
The nucleophilic compound attacks the α,β-unsaturated aldehyde/ketone at the carbonyl carbon (and does NOT interact with the alkenyl group).
1,4–Addition
Conjugate Addition
The alkenyl group AND the aldehyde/ketone group of the α,β-unsaturated carbonyl are involved in the addition reaction.
The nucleophilic compound attacks the α,β-unsaturated aldehyde/ketone at the β–carbon to create an enol intermediate.
Nucleophiles: 1,2–Addition
- H2O
- Alcohols
- Thiols
- 1°/2° Amines
- Cyanides
- Organocuprates
- Grignard Reagents
- Enolates
The 1,2–Addition pathway is preferred by stronger nucleophiles. (Hydroxylamine and Hydrazine are EXCEPTIONS!)
Nucleophiles: 1,4–Addition
- Grignard Reagents
- Organolithiums
- Metal Hydrides
- Hydroxylamine
- Hydrazine
The 1,4–Addition pathway is preferred by weaker nucleophiles. (Hydroxylamine and Hydrazine are EXCEPTIONS!)
α,β-Unsaturated Carbonyls as Alkenyls and Aldehydes/Ketones
The α,β-unsaturated aldehyde/ketone experiences 1,4-addition if it reacts with a weaker nucleophilic compound.
The weaker nucleophilic compound attacks the α,β-unsaturated aldehyde/ketone at the β–carbon to create an enol intermediate. Subsequent deprotonation and π-electron rearragement results in the formation of a simple aldehyde/ketone.
Why are Grignard reagents able to attack at the α,β-unsaturated carbonyl at the β–carbon OR the carbonyl carbon?
Grignard reagents are medium-strength nucleophiles (i.e. weaker nucleophiles than organolithium reagents and stronger nucleophiles than organocuprate reagents).
Since the Grignard reagent is a weaker nucleophile than the 1,2–preferring organolithium reagent and a stronger nucleophile than the 1,4–preferring organocurprate reagent, it has the ability to perform both types of nuclephilic addition.
Reactions of α,β-Unsaturated Carbonyls: Grignard Reagents
Nucleophilic Addition to α,β-Unsaturated Carbonyls
Grignard reagents can undergo 1,2-addition AND 1,4-addition to α,β-unsaturated aldehydes/ketones.
Grignard reagents are weaker nucleophiles than the 1,2–preferring organolithium reagents and stronger nucleophiles than the 1,4–preferring organocurprate reagents.
Why do stronger nucleophiles prefer to undergo 1,2–Addition?
Nucleophilic Addition to α,β-Unsaturated Carbonyls
- The carbonyl carbon is more positively charged than the β-carbon, so the nucleophile will attack the carbonyl carbon faster/earlier.
- Attack of the stronger nucleophilic compound is highly exothermic due to the formation of the robust C—Nu bond, so the reaction is irreversible.
The carbonyl carbon has a greater partial positive charge (than the β-carbon) since it is directly bonded to the electronegative Oxygen aotm.
1,2–Addition: Thermodynamic Control vs. Kinetic Control
Nucleophilic Addition to α,β-Unsaturated Carbonyls
Kinetic Control
The nucleophile will always attack the carbonyl carbon first due to it possessing a greater partial positive charge. (Unless the nucleophilic addition reaction is reversible, the less stable 1,2-addition product will predominate.)
1,4–Addition: Thermodynamic Control vs. Kinetic Control
Nucleophilic Addition to α,β-Unsaturated Carbonyls
Thermodynamic Control
Although the nucleophile will always attack the carbonyl carbon first, the addition reaction becomes reversible under thermodynamic control. (The thermodynamically more stable 1,4-addition product will predominate since any 1,2-addition reaction will be reversible.)
Addition to α,β-Unsaturated Carbonyls: Hydroxylamine and Hydrazine
Hydroxylamine and Hydrazine prefer to undergo 1,2–addition to the α,β-unsaturated aldehyde/ketone (despite being weaker nucleophiles) since the 1,2–product is thermodynamically more stable.
The Oxime (i.e. the 1,2-addition product of Hydroxylamine) and Hydrazone (i.e. the 1,2-addition product of Hydrazine) are stabilized via conjugation between the OH/NH2 π-electrons and the C=N π-bond.
During the protonation step of 1,4–addition, why does the enolate become protonated faster than the α-carbon?
Nucleophilic Addition to α,β-Unsaturated Carbonyls
The enolate (with a full negative charge) is more negatively charged than the α–carbon (with a partial negative charge).
Oxime
A compound containing a Carbon double-bonded to a Nitrogen (C=N) that is single-bonded to an alcohol group (—OH).
R2—C=N—OH
Reagents: Organocuprate Preparation
Organocuprate = R2CuLi
2 R—Li + CuI
Reactions of Organocuprates
- β–Alkylation (via Acid Workup)
- α,β–Dialkylation (via Addition of Alkyl Halide)
α,β-Unsaturated Carbonyl → 1,5-Dicarbonyl
Michael Addition
The Michael Addition reaction occurs under basic conditions ONLY.
Aldehyde/Ketone → 1,5-Dicarbonyl
Michael Addition
The Michael Addition reaction occurs under basic conditions ONLY.
Reagents: Michael Addition
Starting Materials: α,β-Unsaturated Carbonyl + Aldehyde/Ketone
CH3CH2O–, CH3CH2OH
The α,β-unsaturated carbonyl must consist of four carbons.
Ethoxide Deprotonation in Michael Addition
Since the ethoxide base is relatively unhindered, it will deprotonate the most substituted α-carbon (to form the most stable enolate intermediate).
α,β-Unsaturated Carbonyl → Cyclic α,β-Unsaturated Ketone
Robinson Annulation
The Robinson Addition mechanism occurs under basic conditions and at high temperatures ONLY.
Aldehyde/Ketone → Cyclic α,β-Unsaturated Ketone
Robinson Annulation
The Robinson Addition mechanism occurs under basic conditions and at high temperatures ONLY.
Mechanism: Robinson Annulation
- Deprotonation of α-Carbon to Aldehyde/Ketone
- 1,4–Addition of Enolate to α,β-Unsaturated Carbonyl
- Protonation of Internal α-Carbon to Enolate
- Deprotonation of Terminal α-Carbon to Ketone
- Ring Formation via Attack by Terminal α-Carbon of Enolate
- Protonation of Oxide
- Deprotonation of α-Carbon to Ketone
- Leaving of Hydroxyl via π-Electron Rearragement
Michael Addition + Intramolecular Aldol Condensation
Reagents: Robinson Annulation
Starting Materials: α,β-Unsaturated Carbonyl + Aldehyde/Ketone
- CH3CH2O–, CH3CH2OH
- CH3CH2O–, Δ (Heat)
The α,β-unsaturated carbonyl must consist of four carbons.
1,5-Dicarbonyl → Cyclic α,β-Unsaturated Ketone
Step 2 of Robinson Annulation
Intramolecular Aldol Condensation
[4 + 2] Annulation
Robinson Annulation
The addition of an aldehyde/ketone to a four-carbon α,β-unsaturated carbonyl yields a six-membered cyclic α,β-unsaturated carbonyl.
In what cases can Robinson Annulation NOT occur?
Robinson Annulation is impossible in cases where NO α-Hydrogens to the non-cyclic ketone are present.
E.g. Robinson Annulation is impossible with compounds containing a phenol group adjacent to the non-cyclic ketone.
Synthons with Nucleophilic α-Carbon
- Enol
- Enolate
- Enamine
- Phosphorus Ylide
Synthons with Electrophilic β-Carbon
- α,β-Unsaturated Aldehyde
- α,β-Unsaturated Ketone
Synthons with Carbanion
- Grignard Reagents
- Organolithium Reagents
- Organocupric Reagents
- Cyanides
Synthons with Carbocation
- Alkyl Halides
- Epoxides
Examples: Carbon-Nucleophiles
- Enol
- Enolate
- Enamine
- Grignard Reagent
- Organolithium Reagent
- Organocupric Reagent
- Cyanide
- Phosphorus Ylide
Examples: Carbon-Electrophiles
- Alkyl Halide
- Aldehyde (Carbonyl Carbon)
- Ketone (Carbonyl Carbon)
- α,β-Unsaturated Aldehyde (β-Carbon)
- α,β-Unsaturated Ketone (β-Carbon)
- Epoxide
- Imine
- Iminium
Protection Groups
- Aldehyde/Ketone: Acetal OR Thioacetal
- Hydroxyl Group: Ether
- Amine: Amide
