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

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.”

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.

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

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.”

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

$\text{Ald./Ket.}+ROH\xrightarrow{H^+}\text{Hemiacetal (HO–C–OR)}$
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.

$\text{Ald./Ket.}+2 ROH\xrightarrow{H^+}\text{Acetal (RO–C–OR)} + H_2O$
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).

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.

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

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

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.

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.

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.

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.

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.