Chemistry of the Carbonyl Group I & II: Nucleophilic Addition

N-Heterocyclic Carbenes (NHCs)

Other Addition Reactions

  • Bisulfite Addition:
    • Sodium bisulfite (NaHSO_3) adds to aldehydes and some ketones.
    • Generates bisulfite addition compounds, which are usually isolated as crystalline solids.

Nucleophilic Addition of Hydride Reagents to Aldehydes and Ketones

  • The formal addition of H^- to an aldehyde or ketone results in a reduction, changing the oxidation level and producing an alcohol.
  • Sodium Borohydride (NaBH_4):
    • Commonly used reagent to achieve these transformations.
    • Any mechanism arrows using BH_4^- as a nucleophile must break a B-H bond, resulting in the formal addition of H^-.
  • When a carbonyl group is the electrophile:
    • Step 1: hydride addition to a carbonyl:
    • Step 2: these reactions are usually carried out in an alcohol / water, which rapidly protonates the tetrahedral intermediate formed after nucleophilic addition to give the product.
  • NaBH_4 is a mild hydride donor.
  • Lithium Aluminum Hydride (LiAlH_4):
    • A more powerful hydride donor.
    • Its mechanism follows an identical pathway, usually carried out in THF solvent.
  • Both reduce carbonyl groups through the formal addition of hydride (H^-) to the carbonyl.

Addition of Organometallic Reagents to Aldehydes and Ketones

  • Organolithium and organomagnesium compounds undergo nucleophilic addition to carbonyls.
  • This generates corresponding alcohols, resulting from the formal addition of "R^-" to the carbonyl group after protonation.
  • Electropositive metals (Li, Mg) in Grignard reagents or organolithium reagents are electron-donating inductive groups.
  • These reagents are nucleophilic at carbon and readily undergo nucleophilic addition to aldehydes and ketones.
  • Mechanism - Organolithium addition (R-Li):
    • Note:
      1. The addition is carried out in THF (aprotic solvent) because organometallic reagents readily react with water / alcohols / H^+ which destroy the organometallic.
      2. Water is added in a separate step after the organometallic (Me-Li in this case) has added to the carbonyl - known as a work-up step - to generate the product alcohol.
  • Organomagnesium reagents (RMgX, where X = Cl, Br, I) are commonly known as Grignard reagents and react similarly to alkyllithiums.
  • Organolithiums and Grignards are good reagents for C-C bond forming processes.
  • How are they made?
    • Grignard reagents are made by adding magnesium turnings to alkyl halides in THF or Et_2O.
    • Mechanism: an oxidative insertion of Mg into the C-halogen bond results in a change in oxidation state of Mg, from Mg(0) to Mg(II).
    • Organolithium reagents are made in a similar fashion by an oxidative insertion reaction from Li metal and an alkyl/aryl halide.
    • Each insertion reaction requires two equivalents of Li and generates an equivalent of the lithium halide salt. The same sort of mechanism as shown above can be postulated.
  • The addition of either Grignard reagents (R-MgX) or organolithium reagents (R-Li) to aldehydes or ketones results in C-C bond formation.

Reaction Asymmetry - Nucleophilic Addition to Aldehydes and Ketones

  • Many addition reactions to carbonyls form products that contain a new stereogenic center at an sp^3 hybridized (tetrahedral) carbon.
  • The product can therefore exist as enantiomers.
  • Do we see a preference for the formation of one enantiomer over the other?
  • The starting ketone is planar (sp^2 hybridized at C), and a nucleophile can add with equal probability from either the “top” or the “bottom” face.
    • The planar "top face"
    • The planar "bottom face"

Chemistry of the Carbonyl Group II

  • Nucleophiles add to carbonyl groups (aldehydes and ketones) to give compounds in which their hybridization has changed from trigonal (sp^2) to tetrahedral (sp^3).
  • However, there are a range of substitution reactions that can occur of a different type in which the carbonyl oxygen (of aldehydes or ketones) is replaced with other groups.
  • Aldehydes and ketones form equilibrium amounts of the hydrate in water.