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 → $\text{Na}<em>2\text{Cr}</em>2\text{O}<em>7$, $\text{K}</em>2\text{Cr}<em>2\text{O}</em>7$.
  • 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: $\text{RCHO} + \text{H}<em>2\text{O} \rightarrow \text{RCH}(OH)</em>2$ (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, $\text{Na}<em>2\text{Cr}</em>2\text{O}_7$, etc.) gives a ketone:
  • $\text{R}<em>2\text{CHOH} \xrightarrow{\text{[O]}} \text{R}</em>2\text{C=O}$
• 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: $\text{SO}<em>3\text{CH}</em>3$ (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: $\text{SO}<em>3\text{C}</em>6\text{H}<em>4\text{CH}</em>3$ (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 $S<em>N1$/$S</em>N2$ 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.