Chapter 22 Reaction Summary Carbonyl Alpha Substitution Reactions Alpha Proton Acidity Trend O O O O O O O O O

RO RO OR H RO H H H H H H pKa = 9 11 13 17 20 25

Decreasing Acidity

Kinetic Versus Thermodynamic Enolates

O NaOR O HOR O LDA room temp THF, -78 °C Thermodynamic Enolate Kinetic Enolate • Thermodynamic Enolate o Contains the more substituted double bond. o Favored with an alkoxide base at room temperature or higher. o Overall the more stable enolate. • Kinetic Enolate o Contains the less substituted double bond. o Favored with a strong base such as LDA at lower temperatures. o The fastest formed, but least stable enolate.

Halogenation at the Alpha Carbon • Acidic Conditions

O X2 O X X2 = Cl2, Br2, or I2 Ph Ph H o Under acidic conditions, mono-halogenation occurs. o The most commonly used acid is acetic acid (CH3COOH), but other acids like HCl and HBr work also. o The mechanism of this reaction proceeds via an enol intermediate. • Basic Conditions O O X2 Ph X2 = Cl2, Br2, or I2 Ph X OH X o Under basic conditions, polyhalogenation occurs replacing all of the alpha protons with halogens. o The mechanism of this reaction proceeds via an enolate intermediate. • Base-Promoted Halogenation of Methyl Ketones (Haloform Reaction) O O O X2 X + HCX Ph 3 X2 = Cl2, Br2, or I2 Ph X Ph O OH X o Under basic conditions, methyl ketones will get tri-halogenated making this carbon a − good leaving group. Hydroxide attacks the carbonyl resulting in the loss of CX3 , which subsequently takes the proton from the RCOOH to yield haloform (HCX3). Elimination of Alpha-Halogens to Form α,β-Unsaturated Carbonyl Compounds O O Pyridine Br

• A halogen α to a carbonyl can be eliminated using a weak base such as pyridine or Li2CO3.

Direct Alpha Carbon Alkylation 1. LDA O THF, -78 °C O 2. R X R Ph Ph • This reaction allows you to put one or more R-groups on the α-carbon. • LDA is the most common base used in the direct alkylation reactions, but alkoxide base can be used if a thermodynamic enolate is desired. • The alkyl halide used must be methyl or primary because the reaction follows an SN2 mechanism.

Malonic Ester Synthesis O O O O O + 1. NaOEt H /H2O mono-α-substituted EtO OEt HO carboxylic acid EtO OEt 2. R-X Δ R R

1. NaOEt 2. R'-X

O O O + H /H2O R' di-α-substituted EtO OEt Δ HO carboxylic acid R R' R • Diethyl malonate is the starting material used in this reaction. • The acidic alpha protons can be substituted by one or two R-groups. • Hydrolysis and decarboxylation yields an α-substituted carboxylic acid.

Acetoacetic Ester Synthesis O O O O O + 1. NaOEt H /H2O mono-α-substituted OEt ketone OEt 2. R-X Δ R R β-ketoester 1. NaOEt 2. R'-X

O O O + H /H2O R' di-α-substituted OEt Δ ketone R R' R • This reaction is identical to the malonic ester synthesis except a β-ketoester starting material is used (rather than a diester). • The product of this reaction is a ketone with one or two R groups at the α-carbon.