05 Aldehydes and Ketones: Nucleophilic Addition

Why carbonyls undergo addition

The carbonyl bond is polarized: oxygen is partially negative, while the carbonyl carbon is partially positive and electrophilic. In Nucleophilic addition, a nucleophile attacks the carbonyl carbon and the $\pi$ electrons move onto oxygen. The carbon changes from trigonal planar, $\mathrm{sp^2}$, to tetrahedral, $\mathrm{sp^3}$, forming an alkoxide intermediate.

The general pattern is:

Protonation of the alkoxide gives an alcohol when the nucleophile forms a single bond to the carbonyl carbon. This is addition rather than substitution: aldehydes and ketones do not have a carbon-based leaving group on that carbon.

An aldehyde has one carbon substituent and one hydrogen, while a ketone has two carbon substituents. Aldehydes are generally more reactive than ketones because they are less crowded and have fewer electron-donating alkyl groups.

Takeaway: The carbonyl carbon is the site of attack, and addition converts the $\ce{C=O}$ group into a tetrahedral center.

Build carbon–carbon bonds with organometallic reagents

A Grignard reagent, $\ce{RMgX}$, or an organolithium reagent, $\ce{RLi}$, acts as a source of nucleophilic carbon. In a Grignard addition, magnesium coordinates to the carbonyl oxygen, helping activate the carbonyl. The reagent’s carbon then attacks the carbonyl carbon, attaching the group $\ce{R}$ to it and creating a new carbon–carbon bond.

The initial product is a metal alkoxide. A separate aqueous or acidic workup protonates the alkoxide to form an alcohol. The carbonyl substrate determines the alcohol class:

• Formaldehyde gives a primary alcohol: $\ce{H2C=O -> RCH2OH}$.

• Another aldehyde gives a secondary alcohol: $\ce{R'CHO -> R'CH(OH)R}$.

• A ketone gives a tertiary alcohol: $\ce{R'COR'' -> R'C(OH)(R)R''}$.

For example, ethylmagnesium bromide adds to ethanal; acidic workup then gives 2-butanol:

These reagents are quenched by water, alcohols, and other acidic proton sources. Keep the reaction anhydrous during addition, and add water or dilute acid only during the later workup.

Takeaway: Use an organometallic reagent to add a carbon group and make a carbon–carbon bond; protect the reagent from proton sources until the addition is complete.

Primary amines form imines

A primary amine adds to an aldehyde or ketone to form a tetrahedral Carbinolamine intermediate. With suitable acid catalysis, the hydroxyl group is converted into water, which can leave; subsequent loss of a proton from nitrogen produces an Imine.

The main steps are:

1. The amine attacks the carbonyl carbon as the $\ce{C=O}$ $\pi$ bond shifts to oxygen.

2. Proton transfers produce the neutral carbinolamine.

3. Protonation of its hydroxyl group allows water to leave, forming an iminium ion.

4. Loss of a proton from nitrogen gives the imine.

The acid level matters. Acid helps make water a better leaving group, but strongly acidic conditions protonate the amine and reduce its nucleophilicity. Imine formation is therefore commonly carried out under mildly acidic conditions. The reaction is reversible, so removing water or using an appropriate excess of a reactant can help favor imine formation.

Hydroxylamine and hydrazine derivatives follow a related pathway, forming oximes and hydrazones, respectively. These derivatives can be useful for identifying carbonyl compounds.

Takeaway: A primary amine generally leads to an imine through a carbinolamine. Mild acidity supports dehydration without excessively suppressing the amine’s nucleophilicity.

Secondary amines form enamines

A secondary amine also adds to a carbonyl and forms an iminium intermediate. Unlike the primary-amine pathway, this intermediate has no nitrogen-bound hydrogen available to lose to give a neutral imine. Instead, a proton is removed from a neighboring $\alpha$-carbon, producing an Enamine with a $\ce{C=C}$ bond next to nitrogen.

A useful prediction rule is that a primary amine generally gives an imine, while a secondary amine generally gives an enamine when an $\alpha$-hydrogen is available.

Takeaway: The amine’s substitution pattern helps determine whether the product is an imine or an enamine; enamine formation requires a suitable neighboring $\alpha$-hydrogen.

Choose a nucleophile to plan a synthesis

Choose a reaction by identifying the target bond and working backward:

• If the target alcohol contains a new carbon substituent at the former carbonyl carbon, consider a Grignard or organolithium reagent. The carbon bearing $\ce{OH}$ came from the carbonyl, and the newly attached carbon group came from the organometallic reagent.

• If the target contains a $\ce{C=N-R}$ group, consider a primary amine.

• If the target contains an enamine unit, consider a secondary amine and check that an $\alpha$-hydrogen is available.

• For organometallic addition, keep the workup step after the reaction. For imine and enamine formation, account for reversibility and the effect of acid on the amine.

Nucleophilic addition offers several ways to transform a carbonyl group: carbon-group addition gives alcohols after workup, primary-amine addition followed by dehydration gives imines, and secondary-amine addition followed by loss of an $\alpha$-proton gives enamines.