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Reactivity of Alpha Hydrogens

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    The alpha carbon is the first carbon atom attached to a functional group, such as a carbonyl. The carbonyl group makes the alpha hydrogen (the hydrogen on the alpha carbon) slightly acidic via a resonance stabilization mechanism. This results in several different reactions of note.

    • Acetoacetic Ester Synthesis
      The acetoacetic ester synthesis allows for the conversion of ethyl acetoacetate into a methyl ketone with one or two alkyl groups on the alpha carbon.
    • Acidity of Alpha Hydrogens & Keto-enol Tautomerism
    • Aldol Reaction
      A useful carbon-carbon bond-forming reaction known as the Aldol Reaction is yet another example of electrophilic substitution at the alpha carbon in enolate anions. The fundamental transformation in this reaction is a dimerization of an aldehyde (or ketone) to a beta-hydroxy aldehyde (or ketone) by alpha C–H addition of one reactant molecule to the carbonyl group of a second reactant molecule.
    • Alpha Alkylation
      The alpha alkylation reaction involves an α hydrogen being replaced with an alkyl group. This reaction is one of the more important for enolates because a carbon-carbon bond is formed. These alkylations are affected by the same limitations as other Sn2 reactions.
    • Alpha Halogenation
      A carbonyl containing compound with α hydrogens can undergo a substitution reaction with halogens. This reaction comes about because of the tendency of carbonyl compounds to form enolates in basic condition and enols in acidic condition. In these cases even weak bases, such as the hydroxide anion, is sufficient enough to cause the reaction to occur because it is not necessary for a complete conversion to the enolate.
    • Claisen Reactions
      Because esters can contain αα hydrogens they can undergo a condensation reaction similar to the aldol reaction called a Claisen Condensation. In a fashion similar to the aldol, one ester acts as a nucleophile while a second ester acts as the electrophile. During the reaction a new carbon-carbon bond is formed; the product is a β-keto ester.
    • Deuterium Exchange
      Due to the acidic nature of α hydrogens they can be exchanged with deuterium by reaction with D2O (heavy water). The process is accelerated by the addition of an acid or base; an excess of D2O is required. The end result is the complete exchange of all α hydrogens with deuterium.
    • Enamine Reactions
      As previously seen, aldehydes and ketones react with 2 o amines to reversibly form enamines.   Example   Reversible     Enamines act as nucleophiles in a fashion similar to enolates.  Because of this enamines can be used as synthetic equivalents as enolates in many reactions.  This process requires a three steps: 1) Formation of the enamine, 2) Reaction with an eletrophile to form an iminium salt, 3) Hydrolysis of the iminium salt to reform the aldehyde or ketone.  Some of the advantages of using an enamine over and enolate are enamines are neutral, easier to prepare, and usually prevent the overreaction problems plagued by enolates.  These reactions are generally known as the Stork enamine reaction after Gilbert Stork of Columbia University who originated the work.     Typically we use the following 2 o amines for enamine reactions
    • Malonic Ester Synthesis
    • Michael Additions & Robinson Annulation
      Enolates undergo 1,4 addition to α, β-unsaturated carbonyl compounds is a process called a Michael addition.  The reaction is named after American chemist Arthur Michael (1853-1942).
    • Synthesis of Enols and Enolates

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