The simplest reactions of alpha carbon are the halogenation of the alpha carbon of a ketone or aldehyde, the Hell-Volhard-Zelinsky reaction, and direct alkylation.
Carbonyl compounds, which have a carbon atom double-bonded to an oxygen atom, undergo two main types of reactions under basic conditions: substitution and condensation at the alpha carbon. An alpha carbon is the carbon atom that is directly attached to the carbonyl group. The location of the alpha carbon in relation to the C=O makes the hydrogens attached to the alpha carbon (the alpha protons) acidic and readily removable. Reactions with the alpha carbon involve keto-enol tautomerism. Keto-enol tautomerism is the chemical equilibrium between a ketone or aldehyde and an enol. An enolate is anion formed when an alpha hydrogen in the molecule of an aldehyde or a ketone is removed as a hydrogen ion.
Halogenation is a reaction in which a hydrogen is replaced by a halogen. In acid-catalyzed alpha carbon halogenation, a halogen (Br, Cl, or I) is substituted at the alpha carbon, replacing a single hydrogen. These reactions functionalize the alpha carbon and provide a precursor for elimination reactions resulting in alpha,beta-unsaturated carbonyls.
Base-catalyzed halogenation of carbonyl compounds often leads to multiple substitutions, which is generally undesirable. Base-catalyzed halogenation in a haloform reaction is a useful mechanism to identify a methyl ketone by its conversion to a carboxylic acid (−COOH).
The haloform reaction is a cleavage of a methyl ketone by Br2, Cl2, or I2 to form CHX3 (where X is Br, Cl, or I). The haloform reaction consists of three steps:
1. The enolate undergoes electrophilic attack by a halogen until the alpha carbon is completely halogenated.
2. The molecule undergoes nucleophilic acyl substitution by −OH, with a CX3 leaving group, stabilized by three electron-withdrawing groups.
3. The −CX3−anion deprotonates the carboxylic acid formed in Step 2 and forms the haloform.
Mechanism of the Haloform Reaction
The Hell-Volhard-Zelinsky (HVZ) halogenation reaction is a halogenation of a carboxylic acid catalyzed by phosphorus trihalide. In one version of the HVZ reaction, PBr3 is added as a catalyst, followed by the addition of one molar equivalent of Br2. An addition reaction is a reaction in which two or more reactants combine to form products. A carboxylic acid bromide forms from the replacement by PBr3 of the −OH with a bromide. Acyl bromide tautomerizes to an enol, which results in bromination, a second time, at the alpha carbon.
Hell-Volhard-Zelinsky Halogenation Reaction
Alkylation is a reaction in which an alkyl group is transferred from one molecule to another organic compound. In a direct alkylation of a carbonyl compound, an enolate acts as a nucleophile in an SN2 reaction in which an alkyl group replaces an alpha proton. The mechanism is a two-step process:
1. An enolate forms.
2. The SN2 attack by the alkyl group occurs in the presence of a strong base, such as lithium diisopropylamide (LDA). Use of a weaker base could result in multiple alkylations.