Carbon Nucleophiles

There are three major classes of carbon nucleophiles:

• organolithium and Grignard reagents
• potassium cyanide and hydrogen cyanide
• phosphorus ylides and phosphonate ester carbanions

Organolithium and Grignard reagents will convert a ketone into a tertiary alcohol or turn an aldehyde into a secondary alcohol via a nucleophilic addition reaction called a Grignard reaction. A tertiary alcohol is an alcohol with three alkyl groups attached to the carbon connected to the alcohol. A secondary alcohol is an alcohol with two alkyl groups attached to the carbon connected to the alcohol. The Grignard reaction is a reaction of a Grignard reagent with a carbonyl-containing compound to yield either an alcohol or another (different) carbonyl. The Grignard reagent is a reagent that has the formula ${\rm{R{-}MgX}}$, where the halogen may be ${-}{\rm{Cl}}$, ${-}{\rm{Br}}$, or ${-}{\rm {I}}$.

The nucleophilic addition of organometallic reagents to aldehydes and ketones is a bit unique because the bond between the carbon and the metal (lithium or magnesium) is very polarized toward the carbon, making the carbon the nucleophile. The nucleophilic carbon of the organometallic donates its electron pair from the $\sigma$ bond between itself and the metal to the electrophilic carbon of the carbonyl. This donation breaks the bond, leaving a positively charged metal complex, and causes the $\pi$ bond between the electrophilic carbon and the oxygen to break, which results in the shared electrons moving to the oxygen of the carbonyl. The positively charged metal complex then coordinates with the negatively charged oxygen of the carbonyl until the oxygen is protonated, creating the final alcohol product. Potassium cyanide and hydrogen cyanide will attack a ketone or aldehyde, turning it into a cyanohydrin, which can undergo subsequent conversion to an alpha-hydroxy carboxylic acid, a beta-amino alcohol, or an alpha, beta-unsaturated carboxylic acid. Wittig reactions and the Horner-Wadsworth-Emmons reaction use a phosphorus ylide or phosphonate ester carbanion to turn an aldehyde or ketone into an alkene.

The nucleophilic addition of cyanide ion to carbonyl groups is a very straightforward nucleophilic attack and generates a cyanohydrin. A cyanohydrin is a functional group containing both cyano and hydroxyl groups. The utility of this reaction lies in the fact that it is reversible and that cyanohydrins are useful synthetic intermediates.

The nitrogen of the cyanide donates an electron pair to the electrophilic carbon of the carbonyl. The donation causes the $\pi$ bond between the electrophilic carbon and the oxygen to break, which results in the shared electrons moving to the oxygen of the carbonyl. The negatively charged oxygen is then protonated in a separate step to create the final cyanohydrin product. This reaction is reversible, and the reaction equilibrium only favors products that are not sterically hindered: products with small substituents rather than large ones. The Wittig reaction is one of the most useful reactions for converting aldehydes and ketones to alkenes. This reaction involves an ylide, a species with opposite formal charges on adjacent atoms. For the Wittig reaction, the ylide is methylenetriphenylphosphorane (${\rm{Ph_3P{=}CH_2}}$). While the ylide is often written as having a double bond between the carbon and phosphorous, this is just one resonance form. The other resonance form has a positive charge on the phosphorus and a negative charge on the carbon, making the carbon nucleophilic. The nucleophilic carbon donates an electron pair to the electrophilic carbon of the carbonyl. The donation causes the $\pi$ bond between the electrophilic carbon and the oxygen to break, which results in the shared electrons moving to the oxygen of the carbonyl. The negatively charged oxygen then donates an electron pair to the positively charged phosphorus, creating a four-membered ring. This ring undergoes reverse [2+2] cycloaddition and quickly breaks down. The $\sigma$ bonds between the oxygen and the electrophilic carbon and between the phosphorus and the nucleophilic carbon break, and new $\pi$ bonds between the oxygen and the phosphorus and between the two carbons form to give the final alkene product along with the triphenylphosphine oxide by-product. The Wittig reaction has a modification known as the Horner-Wadsworth-Emmons reaction, which is similar to the Wittig reaction but uses a stabilized phosphonate ester carbanion in place of an ylide. Additionally, while the Wittig reaction tends to be selective for Z-alkenes, the modification tends to select for E-alkenes.