Carbonyl Chemistry Flashcards
The different types of reactions involving the carbonyl group
Keto-enol tautomerization
Movement of the carbonyl double bond to the α carbon and the movement of the α hydrogen to the carbonyl oxygen.
Conjugate enolisation
- Tautomerization that occurs through the conjugation of an alkyl chain.
- Can be explained by the resonance forms of a ketone/enol.
- Enolisation removes the γ-hydrogen.
- The carbonyl is α-β unsaturated.
Electrophilicity/nucleophilicity of keto-enol forms
Keto form= electrophilic
Enol form= nucleophilic
Lithium diisopropyl amine (LDA)
- A very strong (and bulky) base used to convert enols to enolates
- Not nucleophilic due to bulk so is a terrible nucleophile but good base.
Malonate chemistry starting material
Diester (e.g. diethyl malonate)
Malonate chemistry product
Carboxylic acid
Malonate chemistry basic steps
- Enolization with a matching base (e.g. NaOEt for EtO-COCH2CO-OEt).
- Alkylation with haloalkane (R-X)
- Saponification with hydroxide then H+ (cleaves ester leaving -OH)
- Protonation (H3O+), then decarboxylation with heat of the diacid (cuts off one of the carboxylic acid groups)
- Enol tautomerises to form a ketone.
How to make carbocyclic carboxylic acids
- Use malonate chemistry
- Use an electrophile with two leaving groups (e.g. Br(CH2)3Br)
Retrosynthesis for malonate chemistry
- α or α,α- disubstituted acetic acid starting material.
- Cut at the α-carbon to:
a. reform diester
b. reform any alkyl side chains
How to deprotonate β-keto esters
Use a matching alkoxide.
Using the wrong alkoxide will:
- cause ester exchange creating a mixture of enolates
- causes saponification (OH- only)
Haloform reaction starting materials
Methyl ketone + halogen
Haloform reaction steps
- Convert a methyl ketone to an enolate (use a base like -OH)
- The enolate attacks the halogen and a halogen atom is added
- Tautomerisation restores the carbonyl group
- Repeat 2-3 more times to produce a CX3
- Addition of -OH forms a tetrahedral intermediate where the CX3 will leave in an elimination reaction
- CX3- removes a hydrogen from the newly formed carboxylic acid producing CXH (haloform) and a carboxylate.
- Protonate with H3O+
Remember: CX3 is a good leaving group as the C is slightly positive so can attract the electrons as it leaves
Deuteration
- replace all α-hydrogens with deuterium
- performed by tautomerisation then addition of deuterium to the double bond
- LDA used as a base
Hell-Volhard-Zelinsky starting material
Carboxylic acid
Hell-Volhard-Zelinsky product
α-halogenated carboxylic acid (or ester if a alkoxide is used)
Hell-Volhard-Zelinsky Steps
- Halogen (from something like PBr3) replaces the hydroxyl group.
- Keto-enol tautomerism produces an enol.
- The enol can act as a nucleophile to add a halogen to the α-carbon.
- The oxygen containing species (e.g. H2O, OMe) attacks the carbonyl group forming a tetrahedral intermediate.
- The halogen on the carbonyl carbon leaves and the carbonyl group is reformed.
Addition of an alkyl group to ketone, ester or amide- alkyl group requirements.
The alkyl group must fulfil one of the following criteria:
- must have a good leaving group (e.g. halogen)
- primary alkyl group
- allylic alkyl group
- benzylic alkyl group
Addition of an alkyl group to ketone, ester or amide- steps
- React enol with LDA to form an enolate.
- The enolate acts as a nucleophile to attack the alkyl halide, replacing the hydrogen in the original compound with the alkyl group.
NOTE: this occurs via the SN2 pathway
Aldol reaction starting materials
- Aldehyde= electrophile
- Enolate= nucleophile
Aldol reaction product
β-hydroxy-aldehyde (aldol)
Aldol reaction steps
- Enolate acts as a nucleophile and attacks the carbonyl of the aldehyde producing a tetrahedral intermediate.
- Water reacts with the intermediate to form the hydroxy group on the β-carbon.
Aldol condensation starting material
Aldol
Aldol condensation product
α-β unsaturated carbonyl
Aldol condensation steps
- Aldol reacts with H3O+ and heat to protonate the hydroxyl group.
- Under basic conditions the base removes an α-hydrogen causing:
- a double bond to form between the α and β carbons
- the H2O+ to leave
Retrosynthesis for the α-β unsaturated carbonyl and β-hydroxy-carbonyls
- Disconnect the α, β C-C or α, β C=C bond.
- Add hydrogens to the α-carbon
- Turn β carbon into a C=O
Claisen condensation starting materials
- ester enolate
- carbonyl from a second ester
Claisen condensation product
1,3-dicarbonyl compound
Claisen condensation steps
- Formation of an ester enolate using a matching alkoxide.
- Addition of a second molecule of the ester to form a tetrahedral intermediate.
- Elimination of the alkoxide group of the second ester.
- Alkoxide group takes an α-hydrogen causing enolisation and producing an alcohol.
- Protonation forms the 1,3-dicarbonyl.
Diekmann reaction starting material
Diester
Diekmann reaction product
β-keto ester (with the ketone belonging to a cycle)
Diekmann reaction steps
- Use a matching alkoxide to produce an enolate at one end.
- Double bond of the enolate end attacks the other carbonyl producing a tetrahedral intermediate.
- The alkoxide group attached to the same carbon as the O- leaves and the carbonyl is reformed.
Retrosynthesis for the Claisen/Diekmann
- Disconnect the α-β C-C bond.
- Add one hydrogen to the α-carbon.
- Add -OR to the β-carbon to give an ester
Acetoacetate chemistry starting material
methyl-keto-ester (?)
Acetoacetate chemistry product
Methyl ketone
Acetoacetate chemistry steps
- Enolisation of the ester carbonyl using a matching alkoxide.
- The double bond acts as a nucleophile to attack the an alkyl group- adding it to the α-carbon.
- Ester hydrolysis (saponification) of the ester through a tetrahedral intermediate that eliminates the alkoxide and restores the carbonyl.
- Treatment with alkoxide (matching original ester) to deprotonate the hydroxyl group.
- Protonation and heating to “eliminate” the sideways carboxyl group.
- Keto-enol tautomerisation to restore the carbonyl.
Retrosynthesis for acetoacetate chemistry
- Cut the alkyl chains attached to the α-carbon.
- Add an ester group to the α-carbon.
- Add halogens to the alkyl chains.
Michael Reaction starting materials
- Enolate
- α-β-unsaturated carbonyl
Michael reaction product
1,5-dicarbonyl
How does the Michael Reaction proceed?
Through conjugate addition
Michael Reaction steps
- Enolate acts as a nucleophile, attacking the β- carbon of the α-β-unsaturated carbonyl.
- Compounds combine in acidic conditions, reforming the carbonyl.
1,2 vs 1,4 addition
1,2-addition:
- less stable as negative charge is localised on oxygen
- limited to very reactive nucleophiles
- fastest and dominates reactions with strong nucleophiles.
1,4-addition:
- can occur with weak nucleophiles (enolates).
- reversible and under thermodynamic control.
Retrosynthesis for 1,5-dicarbonyls
- Number from one carbonyl to the other
- Disconnect C2-C3 bond
- At add a H to C2 and make C3-C4 a double bond
(It is possible to number in the reverse direction to give different starting materials)
Mannich Reaction starting materials
- Formaldehyde
- Enolizable ketone
- Secondary amine
Mannich Reaction product
Mannich Base
Mannich Reaction Steps
- Protonation of formaldehyde
- Nucleophilic attack at the carbonyl by the secondary amine.
- A second protonation of the hydroxy group
- Elimination of the H2O+ and formation of a double bond (C=N).
- Nucleophilic attack on imminium by enolizable ketone.
Betti Reaction
A Mannich reaction using a phenol rather than an enolisable ketone; the product is a Betti base.
