Carbonyl Chemistry and Reactivity (5D) - MCAT Chemical and Physical Foundations of Biological Systems

Amide. The highly electrophilic acyl chloride undergoes nucleophilic acyl substitution with ammonia or amines, displacing chloride.

Ester. Alcohols act as nucleophiles to attack the acyl chloride, forming the ester after chloride elimination, with base neutralizing HCl.

Ester + carboxylic acid. Alcohol attacks one carbonyl of the anhydride, leading to ester formation and release of the carboxylic acid as the leaving group.

$\text{Cl}^- > \text{RO}^- > \text{NH}_2^-$. Leaving group ability correlates with conjugate acid strength: HCl (strong) > ROH (weak) > NH3 (very weak), enabling easier departure.

Aldehyde has $\text{H}$; ketone has two carbon substituents. Aldehydes have a hydrogen attached to the carbonyl, while ketones have two alkyl or aryl groups, affecting reactivity and naming.

Aldehyde. Aldehydes have less steric hindrance and fewer electron-donating alkyl groups, making their carbonyl carbon more electrophilic.

Alcohol (aldehyde $\rightarrow$ $1^\circ$, ketone $\rightarrow$ $2^\circ$). NaBH4 selectively reduces the carbonyl to an alcohol via hydride addition, yielding primary from aldehydes and secondary from ketones.

No reaction (ketones resist oxidation under mild conditions). Ketones lack an alpha hydrogen attached to the carbonyl like aldehydes, resisting oxidation without carbon-carbon bond cleavage.

Imine (Schiff base). Acid catalysis facilitates nucleophilic addition followed by dehydration to form the C=N bond in the imine.

Enamine. Secondary amines form a carbinolamine intermediate that dehydrates to an enamine via alpha-hydrogen abstraction under acid conditions.

Acetal (via hemiacetal intermediate). Acid protonates the carbonyl, enabling alcohol addition to hemiacetal, followed by further substitution to the acetal with excess alcohol.

The $\alpha$-carbon. The alpha-carbon bears acidic hydrogens stabilized by resonance with the carbonyl in the enolate form.

$\alpha$-hydrogen next to a carbonyl. The alpha-hydrogen is acidified by resonance stabilization of the enolate anion, with pKa around 20 versus 50 for alkanes.

Cyanohydrin. Cyanide acts as a nucleophile adding to the carbonyl, forming a new C-C bond and a hydroxyl group after protonation.

Acyl chloride > anhydride > ester > amide. Electrophilicity decreases due to poorer leaving groups and increased resonance stabilization from the heteroatom lone pair to the carbonyl.

Strong $n_N \rightarrow \pi^*_{C=O}$ donation reduces electrophilicity. This resonance delocalizes electrons, making the carbonyl carbon less electrophilic and less reactive to nucleophiles compared to esters.

Nucleophilic acyl substitution (addition–elimination). The mechanism involves nucleophilic addition to form a tetrahedral intermediate, followed by elimination of the leaving group to reform the carbonyl.

Tetrahedral alkoxide intermediate. Nucleophilic attack on the carbonyl carbon collapses the pi bond, forming a tetrahedral structure before leaving group departure.

Ester. Acid catalysis protonates the carboxylic acid carbonyl, enabling nucleophilic attack by the alcohol followed by water elimination.

Carboxylate + alcohol (saponification). Irreversible base hydrolysis cleaves the ester, yielding the carboxylate salt and alcohol without protonation.

Fischer esterification. This reversible reaction uses acid catalysis to form the ester and water, shifting equilibrium toward products with excess reactants.

Excess alcohol. Le Chatelier's principle shifts the equilibrium toward ester formation by increasing reactant concentration and removing water.

Carboxylic acid + alcohol. Base hydrolysis cleaves the ester to carboxylate and alcohol, with acid workup protonating the carboxylate to the acid.