Reactions of Alcohols – Comprehensive Study Notes

Oxidation of Alcohols (MCAT-Relevant)

  • General idea: Increasing the number of C–O bonds (or decreasing the number of C–H bonds) while an oxidant itself is reduced.
  • Oxidants appear in roughly three strengths on the MCAT:
    • Mild, anhydrous (stops at aldehyde) → Pyridinium chlorochromate (PCC).
    • Strong Cr(VI) salts → \text{Na}2\text{Cr}2\text{O}7, \text{K}2\text{Cr}2\text{O}7.
    • Very strong, acid-dissolved chromium trioxide → Jones oxidation.

Primary alcohols (1° RCH₂OH)

  • PCC:
    • Reaction: \text{RCH}_2\text{OH} \xrightarrow[\text{anhydrous}]\text{PCC} \; \text{RCHO (aldehyde)}
    • Stops here because PCC is used under anhydrous conditions, no water → no hydrate (geminal diol) → no further oxidation.
  • Strong Cr(VI) salts or Jones (CrO₃/H₂SO₄, acetone):
    • Hydration step: \text{RCHO} + \text{H}2\text{O} \rightarrow \text{RCH}(OH)2 (geminal diol)
    • Oxidation: \text{RCH}(OH)_2 \xrightarrow{\text{Cr(VI)}} \text{RCOOH}
    • Net: \text{RCH}_2\text{OH} \rightarrow \text{RCOOH}
  • Redox bookkeeping: Cr(VI) (orange) → Cr(III) (green).

Secondary alcohols (2° R₂CHOH)

  • Any Cr-based oxidant (PCC, CrO₃, \text{Na}2\text{Cr}2\text{O}_7, etc.) gives a ketone:
    • \text{R}2\text{CHOH} \xrightarrow{\text{[O]}} \text{R}2\text{C=O}
  • No over-oxidation because ketones lack a wt-removable hydrogen on carbonyl carbon.

Tertiary alcohols (3° R₃COH)

  • Contain no C–H bond on the carbon bearing OH → cannot be oxidized without breaking C–C bonds.
  • MCAT favorite: "Which alcohol is resistant to oxidation?" → a 3° alcohol.

Mesylates & Tosylates – Turning OH into a Good Leaving Group (and Protector)

  • Problem: \text{OH}^- is a poor leaving group in S_N reactions.
  • Solution: convert to sulfonate esters → resonance-stabilized anions after departure.

Mesylates (MsO-)

  • Functional group: \text{SO}3\text{CH}3 (derived from methanesulfonic acid).
  • Preparation:
    • Reagents: methanesulfonyl chloride (MsCl) + alcohol + base (often triethylamine).
    • Mechanism: alcohol O attacks S; Cl⁻ leaves; base removes proton.
  • Roles:
    1. Great leaving group for nucleophilic substitution or elimination.
    2. Protecting group: resistant to many oxidants/reagents that would attack free OH.

Tosylates (TsO-)

  • Functional group: \text{SO}3\text{C}6\text{H}4\text{CH}3 (para-toluene-sulfonate).
  • Preparation: p-toluenesulfonyl chloride (TsCl) + alcohol + base.
  • Same dual purpose as mesylates.

Why they protect

  • After conversion, molecule no longer behaves as an acid or nucleophile at that position.
  • Particularly useful in multi-step syntheses where selective oxidation/reduction is required.

Alcohols as Protecting Groups for Carbonyls

  • Target: reactive aldehydes (RCHO) & ketones (R₂C=O) may be over-reduced by strong hydrides (e.g., \text{LiAlH}_4).
  • Strategy: convert carbonyl to acetal/ketal by reaction with alcohol(s).

Formation of acetals and ketals

  • Reagents:
    • Either two equivalents of a monohydric alcohol or
    • one equivalent of a diol (e.g., ethylene glycol) under acidic catalysis.
  • Products:
    • Aldehyde + ROH → acetal (1° C attached to two OR groups + one H).
    • Ketone + ROH → ketal (2° C attached to two OR groups).
  • General mechanism: protonate carbonyl → nucleophilic addition of ROH → hemiacetal → substitution to give acetal + water (Le Chatelier driven by removal of water).

Protective power

  • Acetals/ketals are stable to strong bases and strong reducing agents (LiAlH₄) because they lack an electrophilic C=O.
  • After the desired reduction of other functional groups, the acetal/ketal can be removed (“deprotected”) by aqueous acid, regenerating the carbonyl.
    • \text{Acetal} + \text{H}^+ + \text{H}_2\text{O} \rightarrow \text{Carbonyl} + 2 \text{ROH}

Practical / Conceptual Connections

  • Functional group manipulation is a cornerstone of multistep syntheses on the MCAT and in real labs.
  • Oxidation state ladders: \text{Alcohol} \rightarrow \text{Aldehyde} \rightarrow \text{Carboxylic acid} (primary) & \text{Alcohol} \rightarrow \text{Ketone} (secondary).
  • Protecting groups illustrate chemoselectivity: selectively disable a reactive part so another transformation can occur elsewhere.
  • Leaving-group conversion underlies SN1/SN2 strategy questions.

Quick MCAT Tips

  • Remember PCC = anhydrous = stops at aldehyde.
  • Recognize Jones reagent description "CrO₃ in dilute H₂SO₄, acetone".
  • CF3- or sulfonyl chlorides generally indicate mesyl/tosyl formation (think “SO₃” segment).
  • Protect before LiAlH₄ if –CHO or >C=O is present; deprotect with dilute acid.
  • Tertiary alcohol in oxidation multiple-choice → "no reaction" is often correct.