Chemistry of the Carbonyl Group I: Nucleophilic Addition

Chemistry of the Carbonyl Group I: Nucleophilic Addition

N-Heterocyclic Carbenes (NHCs)

  • Introduction to N-Heterocyclic carbenes.

Nucleophilic Addition to Carbonyls

  • Examples of nucleophilic addition to carbonyls, specifically aldehydes and ketones.

Addition of Cyanide

  • Addition of cyanide to aldehydes and ketones yields cyanohydrins.
  • The cyanide ion (-CN) acts as a nucleophile, attacking the electrophilic carbon (C) of the carbonyl group (C=O).
  • This nucleophilic attack leads to the formation of a tetrahedral (sp^3) species.
  • The reaction is typically performed under acidic conditions, which facilitates the protonation of an intermediate, leading to the final product.
  • The reaction is reversible.
  • Aqueous base can catalyze the decomposition of cyanohydrins, regenerating the carbonyl compound and cyanide.
  • Cyanohydrin formation represents an equilibrium between the starting materials and the product.
  • The equilibrium favors aldehyde-derived cyanohydrins more than ketone-derived cyanohydrins.

Addition of Water (Hydration)

  • Aldehydes and ketones undergo hydration, reacting with water to form hydrates.
  • Similar to cyanohydrin formation, hydration is an equilibrium reaction.
  • The equilibrium position is significantly influenced by the structure of the carbonyl compound.
  • Comparison of equilibrium for formaldehyde, acetaldehyde, and acetone:
    • Formaldehyde is almost entirely hydrated at equilibrium due to minimal steric hindrance, which makes the sp^2 to sp^3 hybridization change facile.
    • To understand the variance, the stability of both the starting materials and the hydrate products must be considered.
  • Stability Considerations:
    • Starting Material: Increased substitution leads to increased stability of the carbonyl compound; this trend mirrors that of alkenes. The carbonyl carbon's electrophilicity decreases due to inductive donation from alkyl groups.
    • Hydrate Products: Increased substitution leads to decreased stability of the hydrate due to increased steric hindrance.
  • Aromatic substituted aldehydes: conjugation/delocalization of starting material stabilises carbonyl compound; expect low proportion of hydration product at equilibrium.
  • Aldehydes substituted with electron withdrawing groups (EWG): EWG increase the reactivity of the carbonyl group (make the carbonyl more electrophilic) and lead to extensive hydration.
  • Catalysis:
    • Hydration can be catalyzed by either acid or base.
    • Acid Catalysis: Involves the protonation of the carbonyl group, which enhances the electrophilicity of the carbonyl carbon, making it more susceptible to nucleophilic attack.
    • Base Catalysis: Involves the generation of a stronger nucleophile (e.g., -OH is a better nucleophile than H_2O).

Other Addition Reactions

Bisulfite Addition

  • Sodium bisulfite (NaHSO_3) can add to aldehydes (and some ketones) to produce bisulfite addition compounds, which are usually isolated as crystalline solids.

Hydride Addition

  • Nucleophilic addition of hydride reagents to aldehydes and ketones.
  • The addition of H^- to an aldehyde or ketone is a reduction, leading to the formation of an alcohol.
  • Sodium borohydride (NaBH_4) is a common reagent for these transformations. Any reaction mechanism arrows using BH4- should show the breaking of a B-H bond, to denote the addition of H^-.