Overview
This lecture covers the reactivity of carbonyl groups, focusing on the addition reactions of oxygen- and nitrogen-based nucleophiles to aldehydes and ketones, and connects these reactions to real-world substances like sedatives.
Carbonyl Group Reactivity
- Carbonyl groups have a polar C=O bond, making the carbonyl carbon partially positive and susceptible to nucleophilic attack.
- Nucleophiles such as cyanide, acetylide anions, phosphonium ylides, and others can add to carbonyl carbons.
Addition of Oxygen-Based Nucleophiles
- Water reacts with aldehydes and ketones to form hydrates (geminal-diols); equilibrium usually favors the carbonyl form except in special cases.
- Formaldehyde reacts with water to form formalin, where equilibrium favors the gem-diol due to lack of stabilizing groups.
- Aldehydes with electron-withdrawing groups (e.g., 2,2,2-trichloroacetaldehyde) form stable hydrates like chloral hydrate.
- Alcohols react with aldehydes to form hemiacetals; further reaction leads to acetals in acid-catalyzed conditions.
Hemiacetals, Acetals, and Sugars
- Hemiacetals form when one alcohol adds to a carbonyl; generally unstable except for cyclic forms like sugars.
- Glucose forms two diastereomers (anomers: alpha and beta) as cyclic hemiacetals, with beta favored due to stable chair conformation.
- Acetals are formed by the addition of two alcohols to a carbonyl in acidic conditions; these are stable and used as protecting groups in synthesis.
Addition of Nitrogen-Based Nucleophiles
- Primary amines react with carbonyls to form imines via an acid-catalyzed mechanism.
- Secondary amines react with carbonyls to form enamines, with the final deprotonation on the adjacent carbon.
- Ninhydrin reacts with amino acids to form a purple imine-based dye, useful in fingerprint detection.
Real-World Applications: Sedatives and Synthesis
- Chloral hydrate (a sedative) and diazepam (Valium) involve key carbonyl group reactions.
- Diazepam synthesis involves SN2 displacement of chlorine with ammonia, followed by intramolecular imine formation to close a seven-membered ring.
Key Terms & Definitions
- Carbonyl group — a carbon atom double-bonded to an oxygen atom (C=O).
- Nucleophile — a chemical species that donates an electron pair to an electrophile.
- Geminal-diol (Gem-diol) — a molecule with two hydroxyl (–OH) groups on the same carbon.
- Hemiacetal — compound with one –OR and one –OH group on a former carbonyl carbon.
- Acetal — compound with two –OR groups on a former carbonyl carbon.
- Anomer — type of diastereomer found in sugars, differing at the anomeric carbon.
- Imine — compound with a carbon-nitrogen double bond.
- Enamine — compound with a carbon-carbon double bond adjacent to an amine.
- Protecting group — a group temporarily added to a molecule to block a functional group from reacting.
Action Items / Next Steps
- Review mechanisms for acetal, imine, and enamine formation.
- Prepare for the next lecture on carboxylic acids.