Addition to Carbon-Hetero Multiple Bonds
Nucleophilic addition to carbon-heteroatom multiple bonds (such as $\ce{>C=O}$, $\ce{-C\equiv N}$, and $\ce{-C=N}$) is fundamentally different and much simpler than addition to carbon-carbon multiple bonds because there is generally no regiochemical preference. Because these bonds are highly polar, the carbon atom bears a partial positive charge, acting as the electrophilic center. Consequently, the nucleophilic part of an attacking reagent exclusively attacks the carbon, while the electrophilic part attacks the oxygen or nitrogen. Depending on the nature of the specific 'R' groups attached to the carbonyl, this initial addition can either result in a stable addition product or proceed further to a substitution product via elimination.
1. Addition of Grignard Reagents
Organomagnesium compounds (Grignard reagents) undergo nucleophilic addition to common carbonyl compounds, like aldehydes and ketones, to form a halomagnesium alkoxide intermediate. This intermediate is then hydrolyzed using an acid (like $\ce{H3O+}$) to yield an alcohol. To prevent the subsequent dehydration of highly substituted (tertiary) alcohols, a weak acid like ammonium chloride ($\ce{NH4Cl}$) is frequently used during the aqueous workup. Furthermore, when reacting with $\alpha, \beta$-unsaturated carbonyls, Grignard reagents can yield a mixture of 1,2-addition and 1,4-conjugate addition products.
2. Addition of Organozinc Reagents
Organozinc reagents (dialkylzinc compounds) are notably less reactive towards carbonyl groups compared to Grignard reagents. For instance, reacting diethylzinc with acetaldehyde can take hours to weeks to reach completion depending on the alkyl chain length. However, the nucleophilic addition can be significantly accelerated by utilizing allylzinc reagents or by introducing metal halide Lewis acid catalysts such as $\ce{MgBr2}$, $\ce{TiCl4}$, or $\ce{Ti(O^iPr)4}$.
3. Addition of Organolithium Reagents
Organolithium reagents are far more reactive and powerful than their organomagnesium counterparts. They react rapidly with carbonyl derivatives to form lithium alkoxides, which yield alcohols upon hydrolysis. Because of their extraordinary reactivity, they can successfully attack highly sterically hindered carbonyls (like camphor) that entirely fail to react with Grignard reagents. Also, unlike Grignard reagents, organolithium reagents do not undergo 1,4-conjugate additions with unsaturated systems; they almost exclusively form 1,2-adducts. One drawback is that their strong basicity can occasionally trigger unwanted $\alpha$-deprotonation.
4. Wittig Reaction
The Wittig olefination is an immensely crucial reaction utilized to transform aldehydes and ketones into alkenes using a triphenyl phosphonium ylide, commonly referred to as the Wittig reagent. A ylide is a zwitterionic compound with opposite charges on adjacent atoms, stabilized by pπ-dπ bonding with the phosphorus atom. The mechanism proceeds through the nucleophilic attack of the ylide carbon onto the carbonyl group, forming a dipolar betaine intermediate. This betaine closes into a four-membered oxaphosphatane ring, which subsequently undergoes irreversible, exothermic cleavage to yield the desired alkene and a stable phosphine oxide by-product. The exact geometry of the resulting double bond (E or Z) is dictated by the stability of the starting ylide.
