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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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the one with the lower priority is indicated by its prefix: 4 © 2011 Pearson Education. .If a compound has two functional groups. Inc.

. Inc.Nomenclature of Ketones The carbonyl is assumed to be at the 1-position in cyclic ketones: 5 © 2011 Pearson Education.

. Inc.If a ketone has a second functional group of higher priority… A few ketones have common names: 6 © 2011 Pearson Education.

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: 7 © 2011 Pearson Education. Inc. .

so they have less stable transition states. 8 © 2011 Pearson Education.Aldehydes Are More Reactive Than Ketones • Steric factors contribute to the reactivity of an aldehyde. Inc. • The carbonyl carbon of an aldehyde is more accessible to the nucleophile. . • Ketones have greater steric crowding in their transition states.

Inc. .The reactivity of carbonyl compounds is also related to the basicity of Y–: 9 © 2011 Pearson Education.

Carboxylic acid derivatives undergo nucleophilic acyl substitution reactions with nucleophiles: 10 © 2011 Pearson Education. . Inc.

Inc.Aldehydes and ketones undergo nucleophilic addition reactions with nucleophiles: This is an irreversible nucleophilic addition reaction if the nucleophile is a strong base 11 © 2011 Pearson Education. .

Inc.A reversible nucleophilic addition reaction: 12 © 2011 Pearson Education. .

and carboxylic acid derivatives 13 © 2011 Pearson Education. .Formation of a New Carbon–Carbon Bond Using Grignard Reagents Grignard reagents react with aldehydes. Inc. ketones.

Grignard reagents are used to prepare alcohols: 14 © 2011 Pearson Education. . Inc.

Inc.Mechanism for the reaction of an ester with a Grignard reagent: 15 © 2011 Pearson Education. .

Inc.Examples of Grignard Reactions 16 © 2011 Pearson Education. .

Inc. .Reaction of Acetylide Ions with Carbonyl Compounds + + NH Na 3 17 © 2011 Pearson Education.

. Inc.Reactions of Carbonyl Compounds with Hydride Ion 18 © 2011 Pearson Education.

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Inc. .Mechanism for the reaction of an acyl chloride with hydride ion: 20 © 2011 Pearson Education.

.Mechanism for the reaction of an ester with hydride ion: Esters and acyl chlorides undergo two successive reactions with hydride ion and Grignard reagents 21 © 2011 Pearson Education. Inc.

.Utilization of DIBALH to Control the Reduction Reaction 22 © 2011 Pearson Education. Inc.

Inc. .The reduction of a carboxylic acid with LiAlH4 forms a single primary alcohol: Acyl chloride is also reduced by LiAlH4 to yield an alcohol 23 © 2011 Pearson Education.

Inc.An amide is reduced by LiAlH4 to an amine Mechanism for the reaction of an N-substituted amide with hydride ion: 24 © 2011 Pearson Education. .

Hydride Reducing Agents 25 © 2011 Pearson Education. Inc. .

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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. Inc.Aldehydes and ketones react with a primary amine to form an imine: This is a pH-dependent nucleophilic addition– elimination reaction 29 © 2011 Pearson Education.

Inc. both [H+] and [NH2OH] have the highest values Decreasing rate: [H+] is decreasing Decreasing rate: [NH2OH] is decreasing 30 © 2011 Pearson Education. .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.

.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 © 2011 Pearson Education. Inc.

Inc. .Enamine Reactions 32 © 2011 Pearson Education.

Inc. .Formation of Imine Derivatives 33 © 2011 Pearson Education.

. Inc.Types of Amine–Carbonyl Addition Products 34 © 2011 Pearson Education.

Inc. .Reductive Amination 35 © 2011 Pearson Education.

Deoxygenation of the Carbonyl Group Called the Wolff–Kishner reduction 36 © 2011 Pearson Education. . Inc.

Inc.Water adds to an aldehyde or ketone to form a hydrate: 37 © 2011 Pearson Education. .

Inc.Mechanism for acid-catalyzed hydrate formation: 38 © 2011 Pearson Education. .

. Inc.Why is there such a difference in the Keq values? 39 © 2011 Pearson Education.

The equilibrium constant for the reaction depends on the relative stabilities of the reactants and products: 40 © 2011 Pearson Education. Inc. .

.Addition of an Alcohol to an Aldehyde or a Ketone 41 © 2011 Pearson Education. Inc.

. Inc.Mechanism for acid-catalyzed acetal or ketal formation: 42 © 2011 Pearson Education.

. Inc.Utilization of Protecting Groups in Synthesis LiAlH4 will reduce the ester to yield an alcohol. but the keto group will also be reduced 43 © 2011 Pearson Education.

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: 44 © 2011 Pearson Education. . Inc.

.An OH group can be protected as a trimethylsilyl (TMS) ether: 45 © 2011 Pearson Education. Inc.

Protection of an OH group in a carboxylic acid as the ester: 46 © 2011 Pearson Education. . Inc.

Inc.Protection of an amino group as the amide: 47 © 2011 Pearson Education. .

Addition of Sulfur Nucleophiles 48 © 2011 Pearson Education. . Inc.

Desulfurization replaces the C—S bonds with C—H bonds: 49 © 2011 Pearson Education. Inc. .

Inc. .The synthetically useful aldehyde anion does not exist But its equivalent is accessible via the thioacetal: 50 © 2011 Pearson Education.

Formation of Alkenes: The Wittig Reaction 51 © 2011 Pearson Education. Inc. .

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Inc.Preparation of the Phosphonium Ylide The phosphonium ylide should be prepared from sterically hindered alkyl halide: Synthetic target: Preferred synthetic approach: 53 © 2011 Pearson Education. .

• The Wittig reaction is completely regioselective. • Stable ylides have a group (C=O) that can share the carbanion’s negative charge. . • Stable ylides form primarily E isomers. Example: 54 © 2011 Pearson Education. Inc. and unstabilized ylides form primarily Z isomers. • This reaction is the best way to make a terminal alkene.

Stereochemistry of Nucleophilic Addition Reaction 55 © 2011 Pearson Education. Inc. .

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. Inc.Disconnections. Synthons. and Synthetic Equivalents 59 © 2011 Pearson Education.

Inc. .A synthetic equivalent is the reagent that is actually used as the source of a synthon 60 © 2011 Pearson Education.

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Inc.bUnsaturated Aldehydes and Ketones 64 © 2011 Pearson Education.Nucleophilic Addition to a. .

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66 © 2011 Pearson Education. . because the conjugate addition is not reversible. Inc.• Nucleophiles that form unstable addition products form conjugated addition products. a Grignard reagent will form the conjugate addition product. • If the rate of direct addition is slowed down by steric hindrance. • Nucleophiles that form stable addition products can form direct addition products or conjugate addition products.

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Inc. .Strong bases form direct addition products with reactive carbonyl groups and conjugate addition products with less reactive carbonyl groups: 68 © 2011 Pearson Education.

.Weak bases form conjugate addition products: 69 © 2011 Pearson Education. Inc.

b-Unsaturated Carboxylic Acid Derivatives 70 © 2011 Pearson Education. .Nucleophilic Addition to a. Inc.

. Inc.bUnsaturated Carbonyl Compounds 71 © 2011 Pearson Education.Enzyme-Catalyzed Additions to a.

b-Unsaturated Carbonyls Michael addition nucleophiles: • Cyanide • Sulfide • Organocuprate • Amine • Halides Direct addition nucleophiles: • Grignard • LAH • Organolithiums 72 © 2011 Pearson Education. Inc. .Addition Reactions to a.

.Metabolism of acetaminophen involves conjugate addition: 73 © 2011 Pearson Education. Inc.