19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation

Cyanohydrins form when HCN adds to carbonyl compounds. This reaction showcases how nucleophiles attack electrophilic carbons, creating new C-C bonds. It's a prime example of how carbonyl groups react, setting the stage for understanding more complex organic reactions.

The resulting cyanohydrins are versatile intermediates in organic synthesis. They can be converted into amines or carboxylic acids, making them valuable building blocks for creating more complex molecules like pharmaceuticals and natural products.

Nucleophilic Addition of HCN: Cyanohydrin Formation

Mechanism of cyanohydrin formation

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• Nucleophilic addition reaction involves the addition of HCN (hydrocyanic acid) to a carbonyl group (aldehydes or ketones)
  • Carbonyl carbon acts as an electrophile due to the polarization of the $\ce{C=O}$ bond
  • Cyanide anion ($\ce{CN-}$) acts as a nucleophile, attacking the electrophilic carbonyl carbon (benzaldehyde, acetophenone)
• Base catalysis often employed to generate the reactive cyanide anion from HCN
  • Common bases used include $\ce{NaOH}$, $\ce{NaCN}$, or $\ce{KCN}$
  • Base deprotonates HCN to form the cyanide anion ($\ce{HCN + OH- -> CN- + H2O}$)
• Nucleophilic addition pathway proceeds as follows:
  1. Cyanide anion attacks the carbonyl carbon, forming a tetrahedral alkoxide intermediate
  2. Protonation of the alkoxide intermediate by water or another protic solvent yields the cyanohydrin product (mandelonitrile, 2-hydroxy-2-phenylpropanenitrile)
     • Protonation step regenerates the base catalyst ($\ce{OH-}$)
• This reaction is reversible, with the equilibrium favoring the cyanohydrin product under acidic conditions

Favorability of cyanohydrin reactions

• Favored due to the stability of the cyanide anion and the formation of a strong $\ce{C-C}$ bond
  • Cyanide anion is a strong nucleophile due to the high electronegativity of nitrogen and the linear geometry of the anion
  • Resulting $\ce{C-C}$ bond formed between the carbonyl carbon and the cyanide carbon is strong and stable
• In comparison, other protic acid additions are less favored due to:
  • Weaker nucleophilicity of the corresponding anions ($\ce{Cl-}$ or $\ce{OH-}$) compared to cyanide (HCl, H2O)
  • Formation of less stable $\ce{C-O}$ or $\ce{C-Cl}$ bonds compared to the $\ce{C-C}$ bond in cyanohydrins

Lewis Acid-Base Interactions in Cyanohydrin Formation

• The carbonyl group acts as a Lewis base, donating electrons to form a bond
• Hydrogen cyanide (HCN) acts as a Lewis acid, accepting electrons to form a bond
• This Lewis acid-base interaction is crucial for the formation of the cyanohydrin
• The resulting cyanohydrin often contains a chiral center, making this reaction useful in asymmetric synthesis

Synthetic applications of cyanohydrins

• Versatile synthetic intermediates that can be converted into various functional groups (primary amines, carboxylic acids)
• Conversion of cyanohydrins to primary amines:
  • Reduction of the nitrile group in a cyanohydrin using $\ce{LiAlH4}$ or catalytic hydrogenation yields a primary amine
  • Useful for synthesizing β-hydroxy amines, which are important in pharmaceutical chemistry (ephedrine, pseudoephedrine)
• Conversion of cyanohydrins to carboxylic acids:
  • Hydrolysis of the nitrile group in a cyanohydrin under acidic or basic conditions yields a carboxylic acid
    • Acidic conditions: Heat the cyanohydrin with a strong acid like $\ce{HCl}$ or $\ce{H2SO4}$
    • Basic conditions: Heat the cyanohydrin with a strong base like $\ce{NaOH}$ followed by acidification
  • Useful for synthesizing α-hydroxy acids, which are important in natural product synthesis and biochemistry (lactic acid, mandelic acid)