Nucleophilic Carbon Reactions

Bases that can deprotonate Terminal Alkynes

1. NaNH2

2. BuLi

Mercury Catalyzed Hydration of Alkynes

Uses HgSO4 as catalyst

forms mercury bridge, adds OH makes an enol

will tautomerize to ketone (acid or base catalyzed)

Partial Hydrogenation of Alkynes

forms alkenes

Lindlar’s: forms Z-alkene

Dissolving Metal (Na/NH3): forms E-alkene

Wittig Reaction

Making:

1. RX + PPh₃ → RPPh₃

2. RPPh₃ + BuLi (or other ba → Wittig Reagent (deprotonated RPPh₃)

Reaction:

• makes alkenes

• negative carbon attacks carbonyl

• O and P join and remove, leaving double bond

• forms Z-alkenes usually between carbonyl carbon and negative carbon

Gilman Reagents

R + Li → RLi; then 2 RLi + CuCl → R2CuLi

Forms R2CuLi, adds 1 R but weaker than Grignard

Better for substitution with alkyl halides, and doesn’t fully alcoholize acid derivatives

Enolate and Enol Halogenation

Enolate (basic) - keeps adding to alpha carbon

Enol (acidic) - will add one to alpha carbon

Aldol Reactions

forms B-hydroxycarbonyl

Aldol Addition:

• form enol or enolate

• a-Carbon attacks other carbonyl

• oxygen protonates forming B-hydroxy group

Aldol Condensation:

• if a-Hydrogen present

• hydrogen removed to form new enolate

• E1Cb swing to remove water and form a-B double bond (enone)

• will form Major Product: Z-alkene

• (or if acid, water protonates then leaves)

Cross-Condensation:

• uses one non-enolizable (no alpha-H) in excess

• and the other added slowly

Intramoecular

• Product depends on structure

• ideal formation: 5-6 member ring

• any less and strain prevents formation

Claisen Condensation

• like aldol, but uses esters (either + other ester or carbonyl)

• forms B-ketoester

• base used is salt of alcohol kicked off at the end

• note: B-ketoester has acidic a-Hydrogen, and so nucleophilic a-C, which can be alkylated with alkyl halogen, then hydrolyzed to form B-ketoacid, which can be decarbed to form ketone

adds ester, kicks off the alcohol, leaves with original ester with ketone at beta

note: base deprotonates the alpha-carbon to drive reaction forward, must be deprotonated later

Mixed Claisen Condensation:

• one must be non-enolizable (no alpha-H), and in excess

• other must be added slowly

Kinetic vs Thermodynamic Product

• Thermodynamic: Zaitsev (more thermally stable)

• Kinetic: Hoffman’s (less steric hinderance)

Low Temp and Strong Base favors Kinetic

Hi Temp and Weak Base favors Thermodynamic

Enone Reactions

product of Aldol Condensation

Carbonyl is electrophilic, but Beta carbon also electrophilic (1,4-nucleophilic addition/conjugate addition); will add to the 4-position (oyxgen is 1)

Carbonyl attack is kinetic

Conjugate attack is thermodynamic

Michael Addition

• reacts with an enone

• instead of attacking carbonyl (aldol), will attack beta-carbon (conjugate addition)

• adds enol at the 4-position (alpha is 1)

• will tautomerize into ketone

Note: can then undergo intramolecular aldol forming a 6-membered ring (called Robinson’s Annulation)

Dieckmann Condensation

• intramolecular Claisen Condensation

• also forms rings

Preparation of Enolates

can use base to deprotonate: Lithium Diisopropylamide (LDA)

Consequences of Enolization

1. Exchange with Deuterium during process

2. Flipping of Stereochemistry during process

3. Racemization is a result of Number 2

a-Halogenation

addition of X to a-Carbon

Using Acid:

• forms enol, double bond will add 1 Halogen

Using Base:

• forms enolate, will use up all alpha-Hs to replace with Halogen

a-Alkylation

Aldehydes and Ketones:

• form enolate with LDA

• enolate Nu can attack alkyl halides via SN2 (base catalyzed)

• Complications:

  • feasible with only primary haloalkanes

  • enolate may undergo Aldol instead

  • Ketones may undergo multiple alkylation or regioisomeric products

• As such, ideal conditions are only one R group attaches so only one alpha-H available

Enamines:

• more stable than enol (will not tautomerize as much)

• nucleophilic even if neutral (base less needed)

• enamine can be hydrolyzed after reaction to return to ketone

• as such, enamine formation, addition, hydrolysis is a valid pathway (carbonyl + secondary amine)

Does not work with alcohols (will just take proton in acid base)

Acetoacetic Ester Synthesis

starts with B-ketoester (ex: ethyl acetoacetate)

• forms enolate, then reacts it with alkyl halides (can add 1 R group, or can be looped to add 2 R groups)

• then treat with acid to hydrolyze ester into carboxylic acid

• heat will decarboxylate leaving behind a ketone

Useful for forming substituted ketones from B-ketoesters

Malonic Ester Synthesis

uses a dibeta-ester

• form enolate, react with alkyl halide (can be looped to add 2 R Groups)

• acidify to convert both groups to carboxylic acids

• heat to decarboxylate one of the groups

• left with substituted carboxylic acid

• almost exact same reaction as Acetoacetic Ester Synthesis