15 Medicinal and Pharmaceutical Chemistry - Acid Chlorides and Anhydrides

Learning Outcomes

  • Recall general structures of acid chlorides and anhydrides.
  • Differentiate reactions of carbonyl compounds and carboxylic acid derivatives.
  • Understand the relative reactivity of carboxylic acid derivatives toward nucleophiles.
  • Know the reaction mechanisms involving nucleophiles and carboxylic acid derivatives.
  • Familiarize with general reactions of acid chlorides and anhydrides.
  • Learn the synthesis of aspirin and paracetamol.

Carboxylic Acid Derivatives

  • Functional groups include:
  • Amides: where Z = -NH₂, -NHR, -NR₂.
  • Esters: where Z = OR' (R' ≠ H).
  • Acid Halides: Z = X, (where X = F, Cl, Br, I) specifically Z = Cl for acid chlorides.
  • Thioesters: where Z = SR' (R' ≠ H).
  • Anhydrides: represented by Z = -O-(CO)-R, e.g., ethanoic (acetic) anhydride.

General Structure & Reactivity

  • Carboxylic acid derivatives have a general structural motif where electronegative atoms create partial positive carbon centers, making them susceptible to nucleophilic attack.
  • Reactions typically lead to the formation of a tetrahedral intermediate:
  • Involves two steps, unlike the SN2 mechanism which is a single step.

Mechanism of Reactions

  • Nucleophilic substitution reactions involve a nucleophile attacking the carbonyl carbon:
  • The transition from reactants to products with the formation of a tetrahedral intermediate.
  • Differences in mechanism: aldehydes and ketones undergo nucleophilic addition reactions without forming tetrahedral intermediates.

Reactivity Trends of Carboxylic Acid Derivatives

  • Reactivity hierarchy among derivatives:
  • Most reactive: Acid chlorides > Anhydrides > Esters > Amides Least reactive.
  • This trend allows for transformations from more reactive to less reactive species (e.g., ester to amide) but not vice versa.

Nucleophiles & Leaving Groups

  • Reactions occur under conditions where the leaving group (Y) is superior to the nucleophile (Nu):
  • Strong nucleophiles can carry out reactions effectively if they are paired with good leaving groups.
  • Nucleophilicity can vary based on charge; charged nucleophiles are generally more reactive than neutral ones.

Reactions of Acid Chlorides

  • Acid chlorides react with various nucleophiles, often involving:
  • Alcoholysis: reaction with alcohols to form esters.
  • Hydrolysis: reaction with water producing carboxylic acids.
  • Aminolysis: reaction with amines yielding amides.
  • These reactions produce HCl along with desired products.

Applications of Acid Anhydrides

  • Can be either symmetrical (from two identical carboxylic acid molecules) or unsymmetrical (derived from different acids).
  • Synthesis reactions can utilize acid anhydrides for the creation of complex structures like pharmaceuticals (aspirin, paracetamol).

Key Examples in Synthesis

  • Aspirin: Synthesized from salicylic acid and acetic anhydride, releasing ethanoic acid.
  • Paracetamol: Formed from the reaction of p-hydroxyaniline and acetic anhydride, also yielding acetic acid as a byproduct.