Alpha Carbon Reactions

Simple Reactions of Alpha Carbons

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 {\rm{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.

Keto-Enol Tautomerism

Keto and enol tautomerism is a feature of alpha carbon reactions. The enol is more reactive because the enol is less stable than the keto form.
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.
In alpha-catalyzed halogenation of a carbonyl compound, a halogen substitutes for an alpha hydrogen at the alpha carbon.
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{-}\rm{COOH} ).

Haloform Reaction

In the haloform reaction, the methyl of a methyl ketone is converted first to a trihalocarbon (CX3) and then to a carboxylate with a haloform (CHX3) as a by-product.
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{-}{\rm{OH}}, with a CX3 leaving group, stabilized by three electron-withdrawing groups.

3. The CX3{-}{\rm {CX}_3}^-anion deprotonates the carboxylic acid formed in Step 2 and forms the haloform.

Mechanism of the Haloform Reaction

In the haloform reaction, an enolate attacks an electrophilic dihalide. Next, a nucleophilic acyl substitution takes place with a trihalocarbon (CX3) leaving group. Finally, the trihalocarbon (CX3) anion deprotonates the carboxylic acid, resulting in a carboxylate that is then protonated to a carboxylic acid (COOH) by an acid work-up and a haloform (CHX3).
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{-}{\rm{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

In the Hell-Volhard-Zelinsky (HVZ) reaction, a carboxylic acid is halogenated to form an alpha-halo carboxylic acid.
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.

Direct Alkylation

In a direct alkylation (adding an alkyl group directly to a carbon), an enolate (deprotonated enol) acting as a nucleophile replaces an alpha hydrogen with an alkyl group in the presence of a strong base.