Organic Chemistry

6th Edition Paula Yurkanis Bruice

Chapter 18
Carbonyl Compounds II
Reactions of Aldehydes and Ketones More Reactions of Carboxylic Acid Derivatives Reactions of a,b-Unsaturated Carbonyl Compounds

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Nomenclature of Aldehydes

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If the aldehyde group is attached to a ring,

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If a compound has two functional groups, the one with the lower priority is indicated by its prefix:

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Nomenclature of Ketones

The carbonyl is assumed to be at the 1-position in cyclic ketones:

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If a ketone has a second functional group of higher priority

A few ketones have common names:

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The partial positive charge on the carbonyl carbon causes that carbon to be attacked by nucleophiles:

An aldehyde has a greater partial positive charge on its carbonyl carbon than does a ketone:

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Aldehydes Are More Reactive Than Ketones

Steric factors contribute to the reactivity of an aldehyde. The carbonyl carbon of an aldehyde is more accessible to the nucleophile. Ketones have greater steric crowding in their transition states, so they have less stable transition states.

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The reactivity of carbonyl compounds is also related to the basicity of Y:

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Carboxylic acid derivatives undergo nucleophilic acyl substitution reactions with nucleophiles:

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Aldehydes and ketones undergo nucleophilic addition reactions with nucleophiles:

This is an irreversible nucleophilic addition reaction if the nucleophile is a strong base

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A reversible nucleophilic addition reaction:

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Formation of a New CarbonCarbon Bond Using Grignard Reagents

Grignard reagents react with aldehydes, ketones, and carboxylic acid derivatives
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Grignard reagents are used to prepare alcohols:

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Mechanism for the reaction of an ester with a Grignard reagent:

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Examples of Grignard Reactions

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Reaction of Acetylide Ions with Carbonyl Compounds

+ + NH Na 3

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Reactions of Carbonyl Compounds with Hydride Ion

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Mechanism for the reaction of an acyl chloride with hydride ion:

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Mechanism for the reaction of an ester with hydride ion:

Esters and acyl chlorides undergo two successive reactions with hydride ion and Grignard reagents

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Utilization of DIBALH to Control the Reduction Reaction

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The reduction of a carboxylic acid with LiAlH4 forms a single primary alcohol:

Acyl chloride is also reduced by LiAlH4 to yield an alcohol

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An amide is reduced by LiAlH4 to an amine

Mechanism for the reaction of an N-substituted amide with hydride ion:

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Hydride Reducing Agents

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Selectivity of Reductions

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Hydrogen cyanide adds to aldehydes and ketones to form cyanohydrins:

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Compared with Grignard reagents and hydride ion, CN is a relatively weak base; therefore, in basic solution

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Aldehydes and ketones react with a primary amine to form an imine:

This is a pH-dependent nucleophilic addition elimination reaction

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Dependence of the rate of the reaction of acetone with hydroxylamine on the pH of the reaction: a pH-rate profile
Composition of the ratedetermining step: Maximum rate is at pH = pKa of +NH3OH; at this pH, both [H+] and [NH2OH] have the highest values

Decreasing rate: [H+] is decreasing

Decreasing rate: [NH2OH] is decreasing

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Aldehydes and ketones react with secondary amines to form enamines:

An enamine undergoes an acid-catalyzed hydrolysis to form a carbonyl compound and a secondary amine 31
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Enamine Reactions

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Formation of Imine Derivatives

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Types of AmineCarbonyl Addition Products

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Reductive Amination

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Deoxygenation of the Carbonyl Group

Called the WolffKishner reduction

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Water adds to an aldehyde or ketone to form a hydrate:

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Mechanism for acid-catalyzed hydrate formation:

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Why is there such a difference in the Keq values?

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The equilibrium constant for the reaction depends on the relative stabilities of the reactants and products:

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Addition of an Alcohol to an Aldehyde or a Ketone

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Mechanism for acid-catalyzed acetal or ketal formation:

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Utilization of Protecting Groups in Synthesis

LiAlH4 will reduce the ester to yield an alcohol, but the keto group will also be reduced
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The keto group is protected as a ketal in this synthesis:

The more reactive aldehyde is protected with the diol before reaction with the Grignard reagent:

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An OH group can be protected as a trimethylsilyl (TMS) ether:

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Protection of an OH group in a carboxylic acid as the ester:

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Protection of an amino group as the amide:

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Addition of Sulfur Nucleophiles

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Desulfurization replaces the CS bonds with CH bonds:

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The synthetically useful aldehyde anion does not exist

But its equivalent is accessible via the thioacetal:

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Formation of Alkenes: The Wittig Reaction

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Preparation of the Phosphonium Ylide

The phosphonium ylide should be prepared from sterically hindered alkyl halide:
Synthetic target:

Preferred synthetic approach:

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 The Wittig reaction is completely regioselective.

This reaction is the best way to make a terminal alkene. Stable ylides form primarily E isomers, and unstabilized ylides form primarily Z isomers. Stable ylides have a group (C=O) that can share the carbanions negative charge.
Example:

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Stereochemistry of Nucleophilic Addition Reaction

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Disconnections, Synthons, and Synthetic Equivalents

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A synthetic equivalent is the reagent that is actually used as the source of a synthon

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Nucleophilic Addition to a,bUnsaturated Aldehydes and Ketones

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 Nucleophiles that form unstable addition products form conjugated addition products, because the conjugate addition is not reversible.

Nucleophiles that form stable addition products can form direct addition products or conjugate addition products.

If the rate of direct addition is slowed down by steric hindrance, a Grignard reagent will form the conjugate addition product.
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Strong bases form direct addition products with reactive carbonyl groups and conjugate addition products with less reactive carbonyl groups:

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Weak bases form conjugate addition products:

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Nucleophilic Addition to a,b-Unsaturated Carboxylic Acid Derivatives

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Enzyme-Catalyzed Additions to a,bUnsaturated Carbonyl Compounds

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Addition Reactions to a,b-Unsaturated Carbonyls

Michael addition nucleophiles: Cyanide Sulfide Organocuprate Amine Halides

Direct addition nucleophiles: Grignard LAH Organolithiums

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Metabolism of acetaminophen involves conjugate addition:

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