1 Overview of Carbonyl Compounds. 1. Kinds of Carbonyl Compounds. a) Aldehydes and ketones. No leaving group attached to carbonyl C. Oxidation state +2. b) Carboxylic acids and their derivatives: esters, amides, acyl chlorides, acyl anhydrides. One leaving group attached to carbonyl C. Oxidation state +3. Nitriles are honorary members of the carboxylic acid family, and have much the same reactivity. c) Carbonates and their derivatives: urethanes (carbamates), ureas. Two leaving groups attached to carbonyl C. Oxidation state +4. d) CO2. 2. Reactivity of carbonyl compounds. a) Basic at O. O reacts with H+ or other Lewis acids such as BF3, etc. Not much else. b) Electrophilic at carbonyl C. Under basic conditions, reacts as is. Under acidic conditions, O is protonated to give a compound even more electrophilic at C. c) Acidic at α -C. Acidic because of electrophilic nature of carbonyl C. Under basic conditions, bases deprotonate immediately to give enolate. Under acidic conditions, protonated on O first, then weak base deprotonates at C to give enol. Both enolate and enol are nucleophilic at C (and O). Addition of Nucleophiles to Ketones and Aldehydes. 1. Nucleophilic addition to aldehydes and ketones. a) Under basic conditions, nucleophiles (usually anionic, except for amines: HO–, RO–, RC≡C–, –C≡N, H3N, RNH2) add to neutral carbonyl compounds. After the addition, the former carbonyl O is protonated to give the product. b) Under acidic conditions, nucleophiles (always neutral) add to protonated carbonyl compounds. H2O, ROH, H3N, RNH2. After the addition, the nucleophilic atom is deprotonated to give the product. 2. Reversible nucleophilic addition to aldehydes and ketones: ROH nucleophiles. a) Carbonyl + H2O + (acid or base) →← hydrate. Slow in pure H2O! Equilibrium favors hydrate only for carbonyl compounds with electron-withdrawing groups on α-C’s, e.g. Cl3CCHO (chloral). b) Carbonyl + ROH + (acid or base) →← hemiacetal. Slow in pure ROH! Equilibrium favors hemi-acetal only for carbonyl compounds with electron-withdrawing groups on α-C’s, e.g. carbo-hydrates. c) RCHO or R2CO + R'OH + cat. H+ →← RCH(OR')2 or R2C(OR')2 + H2O. i) Proceeds through hemiacetal. Equilibrium toward acetal by removal of H2O, pushed toward carbonyl by addition of H2O. ii) Most convenient with diols such as ethylene glycol. Entropy favors second reaction. iii) Can be selective for aldehydes over ketones! Thermodynamically controlled.2 iv) Does not work well for esters or acids! d) Who cares? i) Polysaccharides are made and broken down in this way. Glucose + 4-OH of glucose → maltose →→ starch. Glucose + fructose (anomeric centers linked) → sucrose. ii) Unlike carbonyl compounds, acetals are inert to bases and nucleophiles. So ketone or aldehdye can be converted to acetal, then reaction carried out on another functional group in molecule (e.g., carboxylic ester), then ketone or aldehyde freed up. E.g. ethyl 4-oxo-pentanoate to 5-hydroxy-2-pentanone. 3. Reversible nucleophilic addition to aldehydes and ketones: –CN nucleophile. a) Carbonyl + HC≡N + cat. base →← cyanohydrin. Equilibrium favors product in aldehydes. Ketones are more iffy, but can buy acetone cyanohydrin. Makes a C–C bond! E.g., almonds make mandelic acid from benzaldehyde in this way. 4. Irreversible nucleophilic addition to aldehydes and ketones: –H nucleophile. a) Aldehyde + NaBH4 or LiAlH4 → 1° alcohol. Work-up necessary. b) Ketone + NaBH4 or LiAlH4 → 2° alcohol. Work-up necessary. 5. Reversible nucleophilic addition to aldehydes and ketones: amine nucleophiles. a) Carbonyl + NH3, RNH2, R2NH →← iminium ion. i) proceeds via hemiaminal intermediate ii) very, very rapid iii) equilibrium usually favors starting materials iv) iminium ion is ketohyde analog b) Several possible follow-up reactions. i) Strecker reaction: Addition of –CN gives α-amino nitrile, which can be hydrolyzed to α-amino acid. Makes a C–C bond! Retrosynthetically, an α-amino acid is a retron for a Strecker reaction; disconnect carbonyl–α-carbon bond and α-carbon–N bond, and add =O to former α-carbon to get the starting compound. ii) Reductive amination: Addition of NaBH3CN gives more substituted amine. iii) We can deprotonate α-carbon to give enamine (a N analog of an enol). • Nucleophilic addition to give a hemiaminal is followed by E1 elimination of H2O (H+ comes from C; O is protonated before it leaves). • Equilibrium usually favors carbonyl, but can be pushed toward enamine by removal of H2O. iv) If starting amine was NH3 or RNH2, we can deprotonate N to give imine (a N analog of a carbonyl compound) (a.k.a. Schiff bases) • Equilibrium favors imine for R = hydroxy, alkoxy, or amino groups. (Products called oximes, oxime ethers, or hydrazones.) When R= alkyl, equilibrium usually favors carbonyl, but can be pushed toward imine by removal of H2O.3 • Fastest at near-neutral pH: acidic pH protonates starting material and slows first reaction, basic pH slows protonation of O in hemiaminal and prevents second reaction. c) Imines (Schiff bases) are important biological intermediates. Enamines too (will see later). i) Retinal makes imine with lysine residue of rhodopsin. ii) Conversion of pyruvate to alanine catalyzed by pyridoxal (vitamin B6). 6. Reactions of carbonyls with hard nucleophiles. a) Kinds of hard nucleophiles. i) Acetylides made by deprotonating alkynes. ii) Grignard and organolithium reagents made from halides. b) Aldehyde + RMgBr → 2° alcohol; ketone + RMgBr → 3° alcohol. Work-up necessary. Makes a C–C bond! c) CO2 + RMgBr → carboxylic acid. Makes a C–C bond! 7. Oxidation of aldehydes and ketones. a) 1° and 2° alcohols to aldehydes and ketones with PCC. RCH2OH + PCC → RCHO; R2CHOH + PCC → R2C=O. Cr acts as electrophile toward OH, then acts as leaving group in elimination. b) 1° alcohols and aldehydes to acids with Jones’ reagent. RCHO + CrO3/ H2SO4 → RCO2H. Proceeds through hydrate. 8. Retrosynthetic analysis of alcohols, ketones, carboxylic acids. OOHHOHOHOHO!-D-glucopyranoseOHOHOHOHO"-D-glucopyranoseOHHOOOHOHOHOHD-glucose (dextrose)(anomers) OHOHOOHOOHHOHOOHOOHlactose (!-D-galactopyranosyl-(1"4)-D-glucose)OOHHOHOOHOH!-D-galactopyranose(diastereomer of glucose)4
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