Chapter 21: Alpha Carbons

The alpha position of enols/enolates is nucleophilic Enolates are negative, so more nucleophilic than enols

• Identify all α protons • Remove the proton at the α position and draw the resulting anion • Draw the resonance structure showing the negative charge on the oxygen atom

Reagtents [H3O+] & X2 Cl2, Br2, and I2 (not fluorine) Mechanism Results in halogen addition at the α position of and aldehyde or a ketone If the ketone/aldehyde is asymmetrical, halogen adds to the more substituted alpha carbon

Reagents • [H3O+] & Br2 • Pyridine or t-ButO

Reagents • Br2 & PBr3 (phosphorus tribromide) • H2O Mechanism Performs α-halogenation of a carboxylic acid

Reagents NaOH & Br2 Mechanism Product formed is reactive, so poly-halogenation readily occurs

Reagents • NaOH & Br2 • H3O+ Mechanism Converts methyl ketones into carboxylic acids

Reagents NaOH & H2O Mechanism An aldehyde treated with a strong base is converted to an enolate which exists in equilibrium and attack another aldehyde Enolate attacks at the α position Product features both aldehyde and alcohol groups with the −OH group will be on the beta carbon

Reagents [H3O+ or OH−] & heat Mechanism When aldol product is heated water leaves and a double bond forms

The condensation yields typically better than addition yields

Reagents • NaOH or • LDA Mechanism Two ways to limit outcomes: • One reactant is unhindered without alpha protons • Use LDA as a base to completely convert one ractant to an enolate

Reagents NaOH & heat Mechanism Intramolecular aldol reactions form cyclic compounds ONLY 5 and 6 membered rings will form as others are too unstable

Reagents • RO− • H3O+ Mechanism Condensation reaction involving an ester • Starting ester needs 2 alpha protons to work • NO hydroxide can be used because hydrolysis will result • Alkoxide must match –OR of ester to avoid transesterification

Reagents • Strong alkoxy base or • LDA Mechanism Addition of two different esters Must meet one of two conditions: • One ester must have no alpha protons • Directed Claisen is possible with LDA as base

Reagents • RO− • H3O+ Mechanism Intramolecular Claisen condensation Only favorable for 5 or 6 membered rings

Reagents Kinetic product • LDA, −78°C • RX Thermodynamic product • NaH, 25°C • RX Mechanism Two-step mechansim produces an enolate that attacks the alkyl group in an SN2 reaction Regioselectivity is an issue with asymmetrical ketones and choice of base determines product

Reagents • Ethyl acetoacetate • NaOEt • RX • H3O+, heat Mechanism Installs an acetone goup onto the R group as a terminal methyl ketone Works best with primary alkyl halides Disubstituted products can also be obtained via two successive akylation reactions

Reagents • Diethyl malonate • NaOEt • RX • H3O+, heat Mechanism Installs a carboxylic acid goup onto the R group with an additional carbon atom between the R group and the carbonyl Works best with primary alkyl halides Disubstituted products can also be obtained via two successive akylation reactions

Reagents • RMgBr • H3O+ Mechanism Grignard reagents typically attack the carbonyl carbon resulting in a 1,2 addition

Reagents • R2CuLi (dialkyl lithium cuparate) • H3O+ Mechanism Gillman reagents typically attack the β carbon resulting in a 1,4 addition

Stronger nucleophile gives 1,2 addition Grignard reagent Weaker / less reactive gives 1,4 addition Gilman reagent Stabilized enolates (Michale reaction) give 1,4 addition exclusively

Conjugate 1,4 addition that takes place between a Michael donor and a Michael acceptor • Michael donor- nucleophile that does conjugate addition • Michael acceptor- the α, β-unsaturated carbonyl