Hydrides as Reducing Agents
Lithium aluminum hydride (LiAlH4) is a strong reducing agent. It will donate hydride (“H-”) to any C=O containing functional group.
Examples:
+ 2. H3O 1. LiAlH4 (or just H2O)
1. LiAlH4 2. H2O
ketone secondary alcohol
Hydrides as Reducing Agents
Lithium aluminum hydride (LiAlH4) is a strong reducing agent. It will reduce almost any C=O containing functional group to an alcohol.
Example:
1. LiAlH4 2. H2O
ester One and then another equivalent equivalent adds, of H- adds, unavoidably.
Reduced by
LiAlH4 to an alcohol: aldehyde ketone carboxylic acid ester acyl halide Double Addition of Hydride to Carboxylic Acids and Derivatives
Why?
Ketones and aldehydes are more electrophilic than acids, esters and acyl halides. As soon as a ketone or aldehyde is Lone pair donation by generated, it is immediately reduced oxygen reduces partial again. positive charge on C=O carbon.
Reduced by
LiAlH4 to an alcohol: aldehyde ketone carboxylic acid ester acyl halide
Hydrides as Reducing Agents
Exception: LiAlH4 reduces amides to amines.
Examples:
1. LiAlH4 Mechanism depends slightly on whether amide has an N-H or 2. H2O not. But the result is the same. 1. LiAlH4
2. H2O
Reduced by
LiAlH4 to an alcohol: aldehyde ketone carboxylic acid ester acyl halide Hydrides as Reducing Agents
Sodium borohydride (NaBH4) is a mild reducing agent. It is only capable of reducing aldehydes and ketones.
NaBH4 NaBH4 isn’t as basic as LiAlH4, EtOH so reaction can be conducted in protic solvent, and separate workup step isn’t essential. aldehyde primary alcohol
NaBH4 EtOH Reduced by NaBH4:
ketone secondary alcohol aldehyde ketone
Biological Cofactors as Redox Agents
LiAlH4 isn’t used in biology, but biological reductants are mechanistically similar.
NADH reduces by acting as an H- donor enzyme
NADH NAD+ (derived from niacin, vitamin B ) 3 NAD+ oxidizes by acting as an H- acceptor
Cofactor: A small-molecule “helper” that is required by an enzyme to catalyze a reaction. Many vitamins are cofactors. Sterically Hindered Reducing Agents Stop At Aldehyde
1.
(Chapter 22) “DIBAL-H”
2. H2O ester
carboxylic acid aldehyde
(Chapter 22) LiAlH(OtBu)3 -78 °C acyl halide
Nucleophiles Approach Carbonyl Groups At An Angle
Nuc Nucleophiles are electron donors.
As a nucleophile approaches the C=O electrophile, it will donate electrons to the most available, lowest-energy molecular orbital (the LUMO). Nuc Optimal overlap with the * LUMO is at an angle, above or below the C=O plane. Nucleophile Additions to Carbonyls Generate Racemic Mixtures
(addition to top face)
(addition to bottom face)
50:50 mixture of top- and bottom-face adduct is observed.
Enantioselective Reduction of Ketones Using Chiral Catalysts
Chiral catalysts bring reactants together in specific geometries, to force the preferential formation of one enantiomer over the other.
Example:
1. BH3 (S)-CBS reagent (R)
“RS” “R ” L (S) Reaction generates this enantiomer only.
2. H+ (workup) Enantioselective Reduction of Ketones Using Chiral Catalysts
BH3 2. H2O
product (S)-CBS reagent
Ketone orients larger So H- addition occurs on group away from catalyst. one face, and not the other.