In the world of organic chemistry, certain reactions hold immense importance due to their synthetic versatility and practical application in drug design and industrial synthesis. Unit 5 explores such landmark reactions—reductions, oxidations, rearrangements, and condensations—that form the foundation of modern organic synthesis.
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Understanding the Importance of Synthetic Reactions
Synthetic organic chemistry revolves around the ability to transform one molecule into another with precision. Reactions like reductions, oxidations, and rearrangements are not just laboratory exercises—they are powerful tools that chemists use to create complex structures found in pharmaceuticals, fragrances, and polymers.
Metal Hydride Reductions – The Gentle Yet Powerful Reducers
One of the most important methods for reducing carbonyl compounds involves metal hydrides such as Sodium Borohydride (NaBH₄) and Lithium Aluminium Hydride (LiAlH₄).
Sodium Borohydride (NaBH₄):
This reagent is milder and selectively reduces aldehydes and ketones to alcohols without affecting esters, acids, or nitriles. It is often preferred for sensitive molecules that might decompose under harsher conditions.Lithium Aluminium Hydride (LiAlH₄):
On the other hand, LiAlH₄ is a more vigorous reducing agent. It can reduce esters, carboxylic acids, amides, and even nitriles to alcohols or amines. Its reactivity, however, demands careful handling under anhydrous conditions.
These reactions form the backbone of several pharmaceutical syntheses, where controlled reduction is crucial for obtaining desired intermediates.
Classic Reduction Methods – From Metals to Strong Bases
Clemmensen Reduction
Developed by Erik Clemmensen, this reaction involves the reduction of aldehydes or ketones to hydrocarbons using zinc amalgam (Zn-Hg) and hydrochloric acid. It is an acid-catalyzed process particularly useful for compounds stable under acidic conditions.
Wolff-Kishner Reduction
In contrast, the Wolff-Kishner method achieves the same transformation—conversion of carbonyl groups to methylene groups—under strongly basic conditions using hydrazine (NH₂NH₂) and alkali. It is ideal for molecules sensitive to acid.
Birch Reduction
Named after the Australian chemist Arthur Birch, this reduction utilizes sodium in liquid ammonia with an alcohol as a proton source to partially reduce aromatic rings. The Birch reduction opens the way to non-aromatic cyclohexadienes, essential intermediates in steroid and natural product synthesis.
These reduction methods highlight how chemists choose conditions—acidic, basic, or neutral—based on molecular compatibility.
Oppenauer Oxidation and Dakin Reaction – Controlled Oxidations
Oppenauer Oxidation
This is the reverse of the Meerwein-Ponndorf reduction. It converts secondary alcohols into ketones using aluminium isopropoxide in the presence of a suitable acceptor ketone like acetone. Its mild, selective nature makes it invaluable in the synthesis of steroid hormones and fine chemicals.
Dakin Reaction
The Dakin reaction involves the oxidative conversion of aromatic aldehydes or ketones with hydroxyl groups in ortho or para position into phenolic compounds using hydrogen peroxide under basic conditions. This method is particularly useful in the preparation of hydroquinones and catechols, compounds often used in pharmaceuticals and antioxidants.
Rearrangement Reactions – Molecular Reshuffling at Its Best
Beckmann Rearrangement
In this acid-catalyzed rearrangement, an oxime is converted into an amide. It serves as a crucial step in the synthesis of lactams, including caprolactam, which is the precursor to nylon-6—a widely used synthetic fiber.
Schmidt Rearrangement
Here, a carboxylic acid or ketone reacts with hydrazoic acid (HN₃) to yield amines or amides with the evolution of nitrogen gas. This reaction is central to the preparation of heterocyclic compounds and nitrogen-containing pharmaceuticals.
These rearrangements represent the elegant transformation of functional groups within molecules, providing pathways to complex organic architectures.
Claisen–Schmidt Condensation – Building Carbon Frameworks
A key reaction in carbon–carbon bond formation, the Claisen–Schmidt condensation involves the reaction of an aromatic aldehyde with a ketone in the presence of a base, leading to α,β-unsaturated carbonyl compounds.
These products are crucial intermediates in the synthesis of flavonoids, chalcones, and cinnamaldehyde derivatives. The reaction’s simplicity and versatility have made it a cornerstone in both academic and industrial organic synthesis.