Chapter 18
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Chapter 18 Carbonyl Compounds II Reactions of Aldehydes and Ketones More Reactions of Carboxylic Acid Derivatives Reactions of a , b -Unsaturated Carbonyl Compounds. Organic Chemistry 6 th Edition Paula Yurkanis Bruice. Nomenclature of Aldehydes.

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Organic Chemistry 6 th Edition Paula Yurkanis Bruice

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Chapter 18

Carbonyl Compounds II

Reactions of Aldehydes and Ketones

More Reactions of Carboxylic Acid Derivatives

Reactions of a,b-Unsaturated Carbonyl Compounds

Organic Chemistry

6th Edition

Paula Yurkanis Bruice


Nomenclature of Aldehydes


If the aldehyde group is attached to a ring,


If a compound has two functional groups, the one with the

lower priority is indicated by its prefix:


Nomenclature of Ketones

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

ketones:


If a ketone has a second functional group of higher

priority…

A few ketones have common names:


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:


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.


The reactivity of carbonyl compounds is also related to

the basicity of Y–:


Carboxylic acid derivatives undergo nucleophilic acyl

substitution reactions with nucleophiles:


Aldehydes and ketones undergo nucleophilic addition

reactions with nucleophiles:

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


A reversible nucleophilic addition reaction:


Formation of a New Carbon–Carbon

Bond Using Grignard Reagents

Grignard reagents react with aldehydes, ketones, and

carboxylic acid derivatives


Grignard reagents are used to prepare alcohols:


Mechanism for the reaction of an ester with a Grignard

reagent:


Examples of Grignard Reactions


+

+ NH3

Na

Reaction of Acetylide Ions with Carbonyl Compounds


Reactions of Carbonyl Compounds with Hydride Ion


Mechanism for the reaction of an acyl chloride with

hydride ion:


Mechanism for the reaction of an ester with hydride ion:

Esters and acyl chlorides undergo two successive

reactions with hydride ion and Grignard reagents


Utilization of DIBALH to Control the Reduction Reaction


The reduction of a carboxylic acid with LiAlH4 forms a

single primary alcohol:

Acyl chloride is also reduced by LiAlH4 to yield an alcohol


An amide is reduced by LiAlH4 to an amine

Mechanism for the reaction of an N-substituted amide

with hydride ion:


Hydride Reducing Agents


Selectivity of Reductions


Hydrogen cyanide adds to aldehydes and ketones to form cyanohydrins:


Compared with Grignard reagents and hydride ion, CN– is

a relatively weak base; therefore, in basic solution…


Aldehydes and ketones react with a primary amine to

form an imine:

This is a pH-dependent nucleophilic addition–elimination reaction


Dependence of the rate of the reaction of acetone with

hydroxylamine on the pH of the reaction: a pH-rate profile

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

Composition of the rate- determining step:


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


Enamine Reactions


Formation of Imine Derivatives


Types of Amine–Carbonyl Addition Products


Reductive Amination


Deoxygenation of the Carbonyl Group

Called the Wolff–Kishner reduction


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


Mechanism for acid-catalyzed hydrate formation:


Why is there such a difference in the Keq values?


The equilibrium constant for the reaction depends on the

relative stabilities of the reactants and products:


Addition of an Alcohol to

an Aldehyde or a Ketone


Mechanism for acid-catalyzed acetal or ketal formation:


Utilization of Protecting Groups

in Synthesis

LiAlH4 will reduce the ester to yield an alcohol, but

the keto group will also be reduced


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:


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

ether:


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


Protection of an amino group as the amide:


Addition of Sulfur Nucleophiles


Desulfurization replaces the C—S bonds with C—H

bonds:


The synthetically useful aldehyde anion does not exist

But its equivalent is accessible via the thioacetal:


Formation of Alkenes:

The Wittig Reaction


Preparation of the Phosphonium Ylide

The phosphonium ylide should be prepared from

sterically hindered alkyl halide:

Synthetic target:

Preferred synthetic approach:


  • 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

  • carbanion’s negative charge.

Example:


Stereochemistry of

Nucleophilic Addition Reaction


Disconnections, Synthons, and

Synthetic Equivalents


A synthetic equivalent is the reagent that is actually used

as the source of a synthon


Nucleophilic Addition to a,b-Unsaturated Aldehydes and Ketones


  • 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.


Strong bases form direct addition products with reactive

carbonyl groups and conjugate addition products with

less reactive carbonyl groups:


Weak bases form conjugate addition products:


Nucleophilic Addition to a,b-Unsaturated

Carboxylic Acid Derivatives


Enzyme-Catalyzed Additions to a,b-Unsaturated Carbonyl Compounds


Addition Reactions to a,b-Unsaturated Carbonyls

  • Michael addition nucleophiles:

  • Cyanide

  • Sulfide

  • Organocuprate

  • Amine

  • Halides

  • Direct addition nucleophiles:

  • Grignard

  • LAH

  • Organolithiums


Metabolism of acetaminophen involves conjugate addition:


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