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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Organic chemistry 6 th 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

Organic Chemistry

6th Edition

Paula Yurkanis Bruice


Organic chemistry 6 th edition paula yurkanis bruice

Nomenclature of Aldehydes


Organic chemistry 6 th edition paula yurkanis bruice

If the aldehyde group is attached to a ring,


Organic chemistry 6 th edition paula yurkanis bruice

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

lower priority is indicated by its prefix:


Organic chemistry 6 th edition paula yurkanis bruice

Nomenclature of Ketones

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

ketones:


Organic chemistry 6 th edition paula yurkanis bruice

If a ketone has a second functional group of higher

priority…

A few ketones have common names:


Organic chemistry 6 th edition paula yurkanis bruice

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

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.


Organic chemistry 6 th edition paula yurkanis bruice

The reactivity of carbonyl compounds is also related to

the basicity of Y–:


Organic chemistry 6 th edition paula yurkanis bruice

Carboxylic acid derivatives undergo nucleophilic acyl

substitution reactions with nucleophiles:


Organic chemistry 6 th edition paula yurkanis bruice

Aldehydes and ketones undergo nucleophilic addition

reactions with nucleophiles:

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


Organic chemistry 6 th edition paula yurkanis bruice

A reversible nucleophilic addition reaction:


Organic chemistry 6 th edition paula yurkanis bruice

Formation of a New Carbon–Carbon

Bond Using Grignard Reagents

Grignard reagents react with aldehydes, ketones, and

carboxylic acid derivatives


Organic chemistry 6 th edition paula yurkanis bruice

Grignard reagents are used to prepare alcohols:


Organic chemistry 6 th edition paula yurkanis bruice

Mechanism for the reaction of an ester with a Grignard

reagent:


Examples of grignard reactions

Examples of Grignard Reactions


Organic chemistry 6 th edition paula yurkanis bruice

+

+ NH3

Na

Reaction of Acetylide Ions with Carbonyl Compounds


Organic chemistry 6 th edition paula yurkanis bruice

Reactions of Carbonyl Compounds with Hydride Ion


Organic chemistry 6 th edition paula yurkanis bruice

Mechanism for the reaction of an acyl chloride with

hydride ion:


Organic chemistry 6 th edition paula yurkanis bruice

Mechanism for the reaction of an ester with hydride ion:

Esters and acyl chlorides undergo two successive

reactions with hydride ion and Grignard reagents


Organic chemistry 6 th edition paula yurkanis bruice

Utilization of DIBALH to Control the Reduction Reaction


Organic chemistry 6 th edition paula yurkanis bruice

The reduction of a carboxylic acid with LiAlH4 forms a

single primary alcohol:

Acyl chloride is also reduced by LiAlH4 to yield an alcohol


Organic chemistry 6 th edition paula yurkanis bruice

An amide is reduced by LiAlH4 to an amine

Mechanism for the reaction of an N-substituted amide

with hydride ion:


Hydride reducing agents

Hydride Reducing Agents


Selectivity of reductions

Selectivity of Reductions


Organic chemistry 6 th edition paula yurkanis bruice

Hydrogen cyanide adds to aldehydes and ketones to form cyanohydrins:


Organic chemistry 6 th edition paula yurkanis bruice

Compared with Grignard reagents and hydride ion, CN– is

a relatively weak base; therefore, in basic solution…


Organic chemistry 6 th edition paula yurkanis bruice

Aldehydes and ketones react with a primary amine to

form an imine:

This is a pH-dependent nucleophilic addition–elimination reaction


Organic chemistry 6 th edition paula yurkanis bruice

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:


Organic chemistry 6 th edition paula yurkanis bruice

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

Enamine Reactions


Organic chemistry 6 th edition paula yurkanis bruice

Formation of Imine Derivatives


Types of amine carbonyl addition products

Types of Amine–Carbonyl Addition Products


Organic chemistry 6 th edition paula yurkanis bruice

Reductive Amination


Organic chemistry 6 th edition paula yurkanis bruice

Deoxygenation of the Carbonyl Group

Called the Wolff–Kishner reduction


Organic chemistry 6 th edition paula yurkanis bruice

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


Organic chemistry 6 th edition paula yurkanis bruice

Mechanism for acid-catalyzed hydrate formation:


Organic chemistry 6 th edition paula yurkanis bruice

Why is there such a difference in the Keq values?


Organic chemistry 6 th edition paula yurkanis bruice

The equilibrium constant for the reaction depends on the

relative stabilities of the reactants and products:


Organic chemistry 6 th edition paula yurkanis bruice

Addition of an Alcohol to

an Aldehyde or a Ketone


Organic chemistry 6 th edition paula yurkanis bruice

Mechanism for acid-catalyzed acetal or ketal formation:


Organic chemistry 6 th edition paula yurkanis bruice

Utilization of Protecting Groups

in Synthesis

LiAlH4 will reduce the ester to yield an alcohol, but

the keto group will also be reduced


Organic chemistry 6 th edition paula yurkanis bruice

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:


Organic chemistry 6 th edition paula yurkanis bruice

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

ether:


Organic chemistry 6 th edition paula yurkanis bruice

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


Organic chemistry 6 th edition paula yurkanis bruice

Protection of an amino group as the amide:


Organic chemistry 6 th edition paula yurkanis bruice

Addition of Sulfur Nucleophiles


Organic chemistry 6 th edition paula yurkanis bruice

Desulfurization replaces the C—S bonds with C—H

bonds:


Organic chemistry 6 th edition paula yurkanis bruice

The synthetically useful aldehyde anion does not exist

But its equivalent is accessible via the thioacetal:


Organic chemistry 6 th edition paula yurkanis bruice

Formation of Alkenes:

The Wittig Reaction


Organic chemistry 6 th edition paula yurkanis bruice

Preparation of the Phosphonium Ylide

The phosphonium ylide should be prepared from

sterically hindered alkyl halide:

Synthetic target:

Preferred synthetic approach:


Organic chemistry 6 th edition paula yurkanis bruice

  • 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:


Organic chemistry 6 th edition paula yurkanis bruice

Stereochemistry of

Nucleophilic Addition Reaction


Organic chemistry 6 th edition paula yurkanis bruice

Disconnections, Synthons, and

Synthetic Equivalents


Organic chemistry 6 th edition paula yurkanis bruice

A synthetic equivalent is the reagent that is actually used

as the source of a synthon


Organic chemistry 6 th edition paula yurkanis bruice

Nucleophilic Addition to a,b-Unsaturated Aldehydes and Ketones


Organic chemistry 6 th edition paula yurkanis bruice

  • 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.


Organic chemistry 6 th edition paula yurkanis bruice

Strong bases form direct addition products with reactive

carbonyl groups and conjugate addition products with

less reactive carbonyl groups:


Organic chemistry 6 th edition paula yurkanis bruice

Weak bases form conjugate addition products:


Organic chemistry 6 th edition paula yurkanis bruice

Nucleophilic Addition to a,b-Unsaturated

Carboxylic Acid Derivatives


Organic chemistry 6 th edition paula yurkanis bruice

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


Addition reactions to a b unsaturated carbonyls

Addition Reactions to a,b-Unsaturated Carbonyls

  • Michael addition nucleophiles:

  • Cyanide

  • Sulfide

  • Organocuprate

  • Amine

  • Halides

  • Direct addition nucleophiles:

  • Grignard

  • LAH

  • Organolithiums


Organic chemistry 6 th edition paula yurkanis bruice

Metabolism of acetaminophen involves conjugate addition:


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