L5 Reduction of Carbonyl and Carboxylic Acid Derivatives

Reduction via hydrogenation

Needs a catalyst to acitvate the H-H bond.

It is liked in industry due to being atom efficient and H₂ being cheap

Hydrogenation catalyst types

Heterogeneous - transition metals or salts e.g. Pd,PtO₂. They may also be supported by an inert carrier like charcoal or clay. They arenaturally easy to separate.

Homeogeneous - often soluble TM complexes e.g. Wilkinson’s catalyst (Ph₃P)₃RhCl. Their advantage is ability to tune the ligands for selectivity

Hydride reduction

H^- transferred as a nucleophile. However, H^- is not nucleophilic and NaH, LiH etc are bases not reducing agents. They deprotonate, they do not attack electrophilic centres.

LiAlH₄ features

Able to reduce all common polar functional groups. However, it is very moisture sensitive and produces H₂ in a violent reaction with air (catches fire). Needs to be used in dry, aprotic solvents like Et₂O or THF

LiAlH₄ mechanism for reduction

Li polarises the C=O bond further

NaBH₄ features

Easy to handle white powder that can tolerate protic solvents. It is much less reactive than Lith-Al and is used to chemoselectively reduce aldehydes, ketones in the presence of carboxylic acid derivatives. (Not acid chlorides as they are reactive enough)

NaBH₄ reduction mechanism

DIBAL features

This reagent is electrophilic. It is soluble in organic solvents thanks to the isobutyl.

DIBAL reduction of carbonyl mechanism

It must first coordinate to the carbonyl to make it sp³ hybridised and -vely charged to transfer the hydride.

Borane features

Chemoselective for carboxylic acids over esters.

Borane reduction of carboxyl mechanism

Mechanism for borane reduction at the end is not needed - chemoselectivity factor is more relevant.

Why is bornae chemoselective for carboxylic acids only

The proton movement that happens here is not possible with an alkoxy group - the C-O bond does not break.

Dissolving metal reductions

Dissolving Na in liquid ammonia liberates free electrons.

Free electron reduction mechanism

Each electron added is followed by the addition of a hydrogen(proton).

Use for dissolving metal reagents given their difficulty to use

Larger reagents will attack on the less hindered face of the carbonyl - in this case preferring the thermodynamically less stable product.

The mechanism using free electrons does not get sterically hindered so we massively favour the thermodynamically more stable product.

How can Felkin-Anh selectivity be switched using different reagents

You can use large reducing agents to favour the Felkin-Anh product according to sterics, or use a chelating reducing agent to force the other diastereomeric product.

Reduction of a ketone to a secondary amine

We use a modified reducing agetn so it is not storng enough to just reduce the ketone. The ketone can form an imine in presence of acid (although the pH needs to be kept at a point where the amine is not too protonated) and the imine can then be reduced.

Reduction of a ketone directly to an alkane

3 possible routes

Crucially the top/bottom reactions use acid/base respecitvely, giving some options depending on reagent stability. The last reaction proceeds under neither.