Aldehydes & Ketones Master-Class: Oxidation, Nucleophilic Additions, Acetals, Imines, Wittig

Administrative & Study Logistics

  • Midterm prep strategy
    • Second class session = dedicated problem-solving marathon.
    • Review your returned quiz (handed back at end of class) and visit office hours for questions.
  • Extra–problem sources
    • Instructor’s problems are lifted directly from recommended books (esp. Janice G. Smith – Organic Chemistry); specific chapters listed in syllabus.
    • Message: “If I recommend it, that’s exactly what you should be studying.”

Oxidation & Reduction Fundamentals

  • Oxidizing alcohols → carbonyls
    • \text{1° ROH}\xrightarrow[\text{CH}2\text{Cl}2]{\text{PCC}}\text{Aldehyde} (only mild PCC works; strong Cr(VI) gives carboxylic acid).
    • \text{2° ROH}\xrightarrow[H2O]{\text{PCC\ or\ CrO}3/H^+}\text{Ketone} (either mild or strong reagents OK).
    • 3° alcohols: no oxidation (no α-hydrogen).
  • Further oxidation
    • \text{Aldehyde}\xrightarrow{\text{CrO}_3/H^+}\text{Carboxylic Acid} (aldehyde → acid already “built-in” during strong oxidations of 1° ROH).
  • Friedel–Crafts acylation
    • \text{Ar–H}+RCOCl\xrightarrow{AlCl_3}\text{Aryl Ketone}
    • Carbonyl can be reduced later.
  • Catalytic hydrogenolysis of aryl ketones
    • \text{Ar–CO–R}\xrightarrow[{Pd/Pt/Ni}]{H2}\text{Ar–CH2–R} (acyl group → alkyl).
  • Hydride reductions
    • \text{Aldehyde}\xrightarrow[H2O]{NaBH4}\text{1° alcohol}
    • \text{Ketone}\xrightarrow[H2O]{NaBH4}\text{2° alcohol}
    • LiAlH_4 interchangeable but added in separate dry step.
    • Diagnostic tip: single new R = hydride; two new R = Grignard.

Carbon Nucleophile Review (Grignard)

  • RMgBr + \text{Aldehyde} \rightarrow \text{2° alcohol}
  • RMgBr + \text{Ketone} \rightarrow \text{3° alcohol}
  • Nucleophilic carbon = “C–Mg” bond; step-2 aqueous/acid work-up regenerates neutral product.

Cleaving Alkenes to Aldehydes/Ketones/Acids

  • Ozonolysis (reductive work-up; e.g. \text{Alkene}\xrightarrow[Me2S]{O3}\text{2 Carbonyls} )
    • Mechanistically: simply “insert O” and split; excellent aldehyde generator.
  • Hot KMnO4/\text{H}2O cleavage
    • Same C=C split plus over-oxidation of any vinylic H into \text{−COOH}.
    • Fits mnemonic: “Permanganate usually ends as carboxylic acid unless cold dihydroxylation.”

Oxygen Nucleophiles with Carbonyls (Acid Catalysis Mandatory)

  • Universal first step under H^+: protonate the carbonyl O — eliminates possibility of negative charges.

1. Hydration → Geminal Diols

  • \text{Ald./Ket.}+H_2O\xrightarrow{H^+}\text{Gem-Diol (HO–C–OH)}
  • Mechanism
    1. Protonate C=O.
    2. H2O attack.
    3. De-protonate to regenerate acid.

2. Alcohol Addition → Hemiacetals

  • \text{Ald./Ket.}+ROH\xrightarrow{H^+}\text{Hemiacetal (HO–C–OR)}
  • Importance
    • All carbohydrates (glucose, fructose, galactose, etc.) are cyclic hemiacetals.
    • The anomeric carbon = only carbon bearing two heteroatoms (OH & OR); site of biological reactivity.
  • Cyclic hemiacetal formation
    • Intramolecular version where internal OH acts as nucleophile.
    • Ring size determined by which OH attacks (5-membered = furanose, 6-membered = pyranose).
    • Procedure: number the chain, choose attacking O, draw ring first, then add substituents.

3. Acetal Formation (Two Alcohol Equivalents)

  • \text{Ald./Ket.}+2 ROH\xrightarrow{H^+}\text{Acetal (RO–C–OR)} + H_2O
  • Mechanistic highlights (SN1-like)
    1. Protonate carbonyl.
    2. ROH attack → hemiacetal.
    3. Proton transfer → convert OH to good leaving group.
    4. H2O departure → carbocation.
    5. 2nd ROH attack.
    6. Deprotonate ⇒ acetal + acid regenerated.
  • Use as protecting groups for carbonyls (stable to base & many nucleophiles, removed in acid/water).

Retrosynthesis Tips

  • Locate carbon bearing two OR groups ⇨ that carbon belonged to original carbonyl.
  • Each OR fragment traces back to an alcohol nucleophile; original electrophile = aldehyde or ketone.
  • For hemiacetals same logic, but one OR, one OH.

Nitrogen Nucleophiles (Acid Catalyzed)

  • Only primary & secondary amines react (tertiary lacks N–H for proton transfer).

1. Imines (Schiff Bases) from 1° Amines

  • \text{Ald./Ket.}+RNH2\xrightarrow{H^+}\text{C=N–R (Imine)} + H2O
  • Steps mirror acetal path (add, proton transfer, eliminate water, deprotonate).
  • Water must appear as by-product; good exam check.

2. Enamines from 2° Amines

  • \text{Ald./Ket.}+R2NH\xrightarrow{H^+}\text{Enamine (C=C–NR2)} + H_2O
  • After water loss, N has no proton ⇒ conjugate base abstracts β-H (resonance-stabilized) → C=C formation.

Wittig Reaction (C=O → C=C)

  • Reagents: aldehyde/ketone + phosphorus ylide (phosphorane).
  • Ylide definition: adjacent P^+–C^- whose C bears R group(s).
  • Mechanism
    1. [2+2] cycloaddition to give 4-membered oxaphosphetane.
    2. Collapse → R2C=CR' + OPPh3.
  • Stereochemistry: E (trans) alkene generally favored.

Making the Ylide

  • Step 1 SN2: PPh3 + R–X \rightarrow [PPh3R]^+X^- (needs methyl, 1° or allylic halide).
  • Step 2 Base deprotonation (E1cb style): strong base (e.g. n!\text{BuLi},\ NaH, KOtBu) abstracts α-H ⇒ ylide (P^+!!–!C^-).
  • Electron-withdrawing groups (e.g. carbonyl, ester) adjacent to carbanion stabilize via resonance, enhancing acidity and ease of ylide formation.

Acid Catalysis & Mechanistic Patterns (Across O & N Nucleophiles)

  • First action: protonate carbonyl O.
  • Nucleophile adds once carbonyl is activated.
  • Proton transfers orchestrate conversion of OH to H2O LG and regeneration of catalyst.
  • Loss of H2O → carbocation (SN1) except in hydration/hemiacetal where LG not required.

Exam/ACS Strategy Reminders

  • Recognize patterns:
    • Protonated carbonyl → nucleophilic addition.
    • Two OR → acetal; OR + OH → hemiacetal; O- & N-derived analogs distinguished by heteroatom.
    • Phosphorus in reagent list almost always signals Wittig.
  • Count ring atoms when intramolecular nucleophiles present (5 vs 6 membered confusion common).
  • Work backwards: find carbon bearing two heteroatoms to spot original carbonyl for retrosynthesis.
  • By-product cross-checks: H2O in imine/enamine & acetal formation; OPPh_3 in Wittig.
  • Oxidation state memory aid: PCC stops at aldehyde; any Cr(VI) aqueous keeps going to acid.

Practical/Philosophical Connections

  • Carbohydrate cyclization and anomeric reactivity directly mirror hemiacetal chemistry learned here.
  • Protecting-group logic (acetals) underpins multistep synthesis design and ethical environmental consideration (choose removable protecting groups to lower waste).
  • Wittig’s utility extends to pharma/agrochem where immediate alkene products feed into olefin metathesis or bioactive scaffolds — illustrating how foundational mechanisms scale to real-world innovation.