10 Medicinal & Pharmaceutical Chemistry - Alcohols, Phenols, and Ethers Notes

Learning Outcomes

  • Differentiate between:
  • Primary, Secondary, and Tertiary Alcohols
  • Explain trends in properties of alcohols:
  • Solubility: decreases with increasing alkyl group size.
  • Acidity: weak acids that dissociate slightly in water; increased stability of conjugate base increases acidity.
  • Basicity: related to structure of alcohols.
  • Describe reactions involving alcohols:
  • Dehydration: mechanism includes protonation and loss of water.
  • Oxidation: primary alcohols oxidize to aldehydes, then to carboxylic acids; secondary alcohols oxidize to ketones; tertiary alcohols do not react.
  • Discuss resonance structures of phenol and acidity implications.
  • Understand inductive vs. resonance effects on reaction mechanisms.

Alcohols Overview

  • Occurrence: Commonly found in nature.
  • Functional Group: Hydroxyl group (-OH) attached to a tetrahedral carbon.
  • Classification of Alcohols:
  • Primary: Hydroxyl attached to a primary carbon (e.g., methanol).
  • Secondary: Hydroxyl on a secondary carbon (e.g., isopropyl alcohol).
  • Tertiary: Hydroxyl on a tertiary carbon (e.g., tert-butanol).

Properties of Alcohols

  • Boiling Points: Generally higher than alkanes due to hydrogen bonding.
  • Solubility:
  • Soluble in water (for R ≤ 5 carbons).
  • Solubility decreases with increased alkyl group size.
  • Acidity:
  • Alcohols are weak acids that slightly dissociate in water.
  • Factors affecting acidity:
    • Stability of conjugate base (higher stability → higher acidity).
    • Electron-withdrawing groups increase acidity.
    • Electron-donating groups decrease acidity.

Reactivity and Mechanisms

Alcohol Reactions
  1. Dehydration:
  • Occurs via acid catalysis and heat.
  • 3-Step Mechanism:
    1. Protonation of the alcohol.
    2. Loss of water and formation of a carbocation.
    3. Formation of the alkene by loss of a proton.
  1. Oxidation:
  • Primary Alcohol: Oxidizes to aldehyde, then to carboxylic acid.
  • Secondary Alcohol: Oxidizes to a ketone.
  • Tertiary Alcohol: Generally does not undergo oxidation.
Dehydration Mechanism
  • Step 1: Protonation → alcohol becomes a better leaving group.
  • Step 2: Loss of water forms a carbocation. Stability hierarchy: tertiary > secondary > primary.
  • Step 3: Elimination of a proton forms an alkene, following Zaitsev's rule (more substituted alkene is favored).

Phenols

  • Functional Group: Aromatic ring with -OH group.
  • Acidity: More acidic than alcohols due to resonance stabilization of phenoxide ions.
  • Applications: Used as antiseptics; historically, reduced surgical infection rates when used by Joseph Lister.

Ethers

  • Functional Group: R-O-R′ where R and R′ can be alkyl or aryl groups.
  • Properties:
  • Lower boiling points than alcohols due to lack of hydrogen bonding.
  • Applications: First anesthetics (e.g., diethyl ether); found in fragrances (e.g., anisole).

Inductive and Resonance Effects

  • Inductive Effect: Shifts electron density due to electronegative atoms (like oxygen).
  • Resonance Effect: Involves delocalization of electrons through pi systems; stronger compared to inductive effects.

Applications of Ethanol

  • Antiseptic and Disinfectant:
  • Effective against microorganisms in concentrations of 60% - 70%.
  • Denatures and damages microbial proteins and membranes.
  • Biochemical Context: Ethanol can undergo oxidation in biological systems, relevant in conditions like fetal alcohol spectrum disorders.