Aldehydes and Ketones – Chapter 19 Vocabulary Review

Carbonyl Functionality and Nomenclature (Sections 19.1–19.2)

• Aldehydes and ketones share the carbonyl functional group C=O, making them highly central intermediates in synthetic organic chemistry.
• Distinction:
  • Aldehyde: carbonyl carbon bonded to at least one hydrogen (general formula RCHO).
  • Ketone: carbonyl carbon bonded to two carbon atoms (general formula RCOR').
• Electrophilicity: Both groups are polarized (O is δ⁻, C is δ⁺) and therefore susceptible to nucleophilic attack.
• Nomenclature rules:
  • Suffix “-al” (e.g.
  • ethanal, CH_3CHO).
  • Suffix “-one” (e.g.
  • propanone, CH3COCH3).
  • Locate the carbonyl with the lowest possible number in parent chain; this controls numbering priority over alkyl or halogen substituents.
• Importance: Mastery of naming is critical for interpreting mechanisms, literature, and exams.

Preparation of Aldehydes and Ketones (Section 19.3)

• Aldehydes
  • Oxidation of 1° alcohols: RCH2OH \xrightarrow[\text{PCC}]{\text{CH}2Cl_2} RCHO (PCC prevents over-oxidation to carboxylic acid).
  • Ozonolysis of alkenes: RCH=CHR' \xrightarrow{1) O3 \ 2) (CH3)_2S} RCHO + R'CHO (cleaves double bond, delivers two aldehydes if alkene is terminal).
  • Hydroboration–oxidation of terminal alkynes: RC \equiv CH \xrightarrow{1) BH3 \ 2) H2O2, \, OH^-} RCH2CHO.
• Ketones
  • Oxidation of 2° alcohols: R2CHOH \xrightarrow{\text{Na}2Cr2O7, H2SO4} R_2C=O.
  • Ozonolysis of internal alkenes: yields two ketones if each vinylic carbon is substituted.
  • Acid-catalyzed hydration of terminal alkynes (tautomerization of enol): RC \equiv CH \xrightarrow{Hg^{2+}, H2SO4, H2O} RCOCH3.
  • Friedel–Crafts acylation: ArH + RCOCl \xrightarrow{AlCl_3} ArCOR (electrophilic aromatic substitution, forms aryl ketone).
• Significance: Selection depends on substrate availability, functional group tolerance, and desired selectivity.

Reactivity of Carbonyl Compounds: Electrophilicity & General Mechanisms (Section 19.4)

• Electrophilicity sources:
  • Resonance: O:^- - C^+ \leftrightarrow O=C; positive charge on C in resonance contributor explains susceptibility to nucleophilic attack.
  • Inductive effect: Oxygen’s high EN withdraws electron density.
• Aldehydes > Ketones reactivity due to:
  • Steric hindrance: ketones have two alkyl groups surrounding carbonyl carbon.
  • Electronic: alkyl groups donate electron density by induction, reducing electrophilicity.
• Basic nucleophilic addition (two-step paradigm):
  1. Nucleophile attacks carbonyl carbon forming tetrahedral alkoxide.
  2. Proton transfer (work-up) protonates alkoxide.
• Equilibrium considerations: If the nucleophile can leave (e.g.
  halide in acyl substitution), reaction may reverse. For aldehydes/ketones, typical nucleophiles (hydride, carbanion, alkoxide) are poor leaving groups ⇒ additions are often irreversible.

Hydrates & Acetal Chemistry (Section 19.5)

• Hydrates (gem-diols): R2C=O + H2O \rightleftharpoons R2C(OH)2. Equilibrium favors carbonyl unless R = H (formaldehyde) or strong EWG (e.g.
  CCl_3CHO).
• Mechanistic guidelines:
  • Acidic medium: avoid creating strong bases—steps proceed via protonated intermediates.
  • Basic medium: avoid generating strong acids—steps proceed through anionic species.
• Acetal formation (protecting strategy):
  • Overall: R2C=O + 2ROH \xrightarrow{H^+} R2C(OR)2 + H2O.
  • Mechanistic sequence (7 steps):
    1–3: protonation → nucleophilic attack → deprotonation ⇒ hemiacetal.
    4–7: protonate OH, elimination of H_2O, second ROH attack, deprotonation ⇒ acetal.
  • Thermodynamics: Simple aldehydes drive equilibrium toward acetals; ketones generally do not (require Dean-Stark, excess ROH, or molecular sieves).
• Cyclic acetals: Employ diols (e.g. ethylene glycol) to form 5- or 6-membered rings—entropically favored relative to two independent ROH molecules; used widely as carbonyl protecting groups because they are:
  • Stable to strong base, nucleophiles, Grignard reagents.
  • Removable (hydrolyzed) under aqueous acid.
• Hemiacetals: Only isolable when cyclic (e.g.
  carbohydrate chemistry) because intramolecular equilibrium favors ring closure.

Imines, Hydrazones, Oximes & Enamines (Section 19.6)

• Imine formation: R2C=O + R'NH2 \xrightarrow{H^+} R2C=NR' + H2O.
  • Steps 1–3: protonation → amine attack → proton transfers → carbinolamine.
  • Steps 4–6: protonate OH, eliminate H_2O, deprotonate N ⇒ imine (Schiff base).
• Subclasses via varied nucleophiles:
  1. Hydrazones: NH2NH2 yields R2C=NNH2.
  2. Oximes: NH2OH yields R2C=NOH.
• Enamine formation (secondary amine): similar mechanism but final deprotonation occurs at an α-carbon, producing R_2C=CR'N(R'') (enamine) instead of C=N.
• Wolff–Kishner reduction: converts C=O → CH2 via hydrazone intermediate. R2C=O \xrightarrow{NH2NH2} R2C=NNH2 \xrightarrow{KOH, \Delta, \text{ethylene glycol}} R2CH2 + N_2.
  • Practical under strongly basic, high-temperature conditions; complimentary to acidic Clemmensen reduction.

Hydrolysis of Protective Derivatives (Section 19.7)

• Universal reversal: Acetals, imines, and enamines revert to parent carbonyls under aqueous acid (typically H_3O^+, 50–80\,°C).
  • Important for multistep synthesis: temporarily mask carbonyl reactivity, execute base-sensitive steps, then reveal.

Thioacetals & Desulfurization (Section 19.8)

• Formation: R2C=O + 2R'SH \xrightarrow{H^+} R2C(SR')2 + H2O; di-thiols give cyclic thioacetals.
• Raney Nickel reduction: R2C(SR')2 \xrightarrow{\text{Raney Ni}} R2CH2 + 2 R'SH.
  • Net “methylene insertion” → powerful method for deoxygenation of carbonyls in presence of acid-labile groups (acetals would hydrolyze under acid whereas thioacetals survive but are removed reductively).

Reduction of Carbonyls to Alcohols (Section 19.9)

• Hydride reagents supply H^- nucleophile.
  • LiAlH_4 (strong, reacts with esters, acids) requires anhydrous ethereal solvents; aqueous work-up.
  • NaBH_4 (milder, selective for aldehydes/ketones) usable in protic solvents.
• Irreversibility: hydride cannot leave; tetrahedral intermediate collapses only toward alkoxide.
• Stereochemistry: new stereocenter creation → racemic mixture in absence of chiral environment (Felkin–Ahn vs.
  chelation control not covered here but examinable).

Carbon–Carbon Bond Formation (Section 19.10)

• Grignard addition: R2C=O + R''MgBr \xrightarrow{1)\;Et2O \ 2)\;H2O} R2C(OH)R''.
  • Creates new C–C bond; powerful for alcohol synthesis.
  • Not reversible: carbanions are poor leaving groups.
• Cyanohydrin formation: R2C=O + HCN \rightleftharpoons R2C(OH)CN.
  • Equilibrium favorable for less hindered carbonyls.
  • Synthetic utility: CN can be transformed into CO2H, CH2NH_2, etc.
  • Safety note: HCN is highly toxic; lab practice uses NaCN + acid or TMSCN.
• Wittig reaction: converts C=O to C=C.
  • Ylide preparation (SN2): Ph3P: + RCH2Br \rightarrow Ph3P^+CH2R Br^- \xrightarrow{BuLi} Ph_3P=CHR.
  • Reaction: Ph3P=CHR + R'COR'' \rightarrow R'CH=CHR + Ph3P=O.
  • Stereochemical outcome:
  • Unstabilized (alkyl) ylide → predominantly Z-alkene.
  • Stabilized (conjugated with EWG) → predominantly E-alkene.
  • Mechanistic intermediate: betaine or oxaphosphetane leading to phosphine oxide driving force (strong P=O bond).

Baeyer–Villiger Oxidation (Section 19.11)

• Reagent: peroxy acid (e.g.
  mCPBA).
• Transformation: R2C=O + R''CO3H \rightarrow R_2C(O)O (insertion of O adjacent to C=O).
  • Ketone → ester; cyclic ketone → lactone.
• Regioselectivity governed by migratory aptitude (ability to shift with electron pair): H > 3° alkyl > 2° alkyl ≈ aryl > 1°.
  • Example: CH3COCH2CH3 \xrightarrow{mCPBA} CH3COOCH2CH3 (ethyl migrates over methyl).
• Conceptual tie-in: resembles rearrangement in RCOOOH \rightarrow RCOOH + O insertion.

C–C Bond Forming vs. Bond Breaking Summary (Section 19.12)

• Forming:
  1. Grignard addition.
  2. Cyanohydrin formation.
  3. Wittig olefination.
• Breaking:
  • Baeyer–Villiger (cleaves C–C adjacent to C=O while forming C–O).
• Strategy insight: Synthetic planning often pairs bond-forming steps with later bond-cleavage to reshape skeleton.

Spectroscopic Characteristics of Carbonyls (Section 19.13)

• IR Spectroscopy
  • Carbonyl stretch: strong, sharp, \sim 1715\,\text{cm}^{-1}.
  • Conjugation lowers frequency (≈ 1680\,\text{cm}^{-1}).
  • Ring strain (cyclobutanone) raises (≈ 1780\,\text{cm}^{-1}).
  • Aldehydic C–H: pair of bands ≈ 2700, 2850\,\text{cm}^{-1} (diagnostic for CHO).
• ^1H NMR
  • α-protons shifted downfield by +1\,ppm due to carbonyl deshielding.
  • Aldehydic proton: singlet/multiplet near 10\,ppm.
• ^{13}C NMR
  • Carbonyl carbon: weak resonance \sim 200\,ppm (broad, low intensity because no attached protons).
  • Useful for confirming presence and type of carbonyl (ester and amide carbons appear slightly downfield of ketone/aldehyde).
• Practical implication: Combined IR + NMR data allow unambiguous identification of carbonyl-containing functional groups in unknowns.

Integrated Ethical & Practical Considerations

• Cyanide toxicity necessitates strict laboratory safety (fume hood, gloves, antidote protocol).
• Raney Ni is pyrophoric when dry—must remain wet with ethanol/water slurry.
• Choice of protecting group (acetal vs. thioacetal) should minimize environmental impact (avoid heavy-metal waste) and cost.
• Green chemistry: Preference for NaBH4 (water-compatible) over LiAlH4 when feasible; use of catalytic hydrogenation (H2/Pd) as alternative reduction.

Cross-Connections & Real-World Relevance

• Biochemistry: Carbonyl transformations mirror enzymatic processes (e.g.
  imine formation in Vitamin B6-dependent transaminations).
• Pharmaceutical synthesis: Wittig reactions widely employed for alkene geometry control in drug molecules (e.g.
  Artemisinin derivatives).
• Materials: Aldehyde-amine condensation forms imine-based covalent adaptable networks (self-healing polymers).
• Analytical chemistry: IR carbonyl peak shifts aid in diagnosing polymer oxidation or degradation.

Quick Reference – Key Numbers & Equations

• Hydride reduction (irreversible): R2C=O + H^- \rightarrow R2C-O^- \xrightarrow{H^+} R_2C-OH.
• Grignard addition general: R2C=O + R''MgBr \rightarrow R2C(OMgBr)R'' \xrightarrow{H2O} R2C(OH)R''.
• Cyanohydrin formation equilibrium constant typically K_{eq} > 1 for aldehydes (varies with sterics).
• Baeyer–Villiger “Criegee intermediate” rearrangement barrier ≈ \sim 15–20\,kcal·mol^{-1} (low → mild conditions workable).