Nucleophilic Acyl Substitution Organic Chemistry 4th Edition Paula Yurkanis Bruice Chapter 17 Carbonyl Compounds I Nucleophilic Acyl Substitution Irene Lee Case Western Reserve University Cleveland, OH ©2004, Prentice Hall

Carbonyl Compounds with Groups that Can Be Replaced by a Nucleophile

Nomenclature of Carboxylic Acids

Acyl Halides Acid Anhydrides 3-methylpentanoyl bromide ethanoyl chloride acetyl chloride 3-methylpentanoyl bromide b-methylvalerylbromide cyclopentanecarbonyl chloride Acid Anhydrides

Esters

Salts of Carboxylic Acids

Cyclic Esters Are Known as Lactones

Amides

Amides with Substituent(s) Bonded to the Nitrogen N-cyclohexylpropanamide N-ethyl-N-methylpentanamide Cyclic Amides Are Known as Lactams a b g d 2-azacyclobutanone b-propiolactam 2-azacyclohexanone d-valerolactam 2-azacyclopentanone g-butyrolactam

Nitriles ethanenitrile acetonitrile methylcyanide benzenecarbonitrile benzonitrile phenyl cyanide 5-methylhexanenitrile d-methylcapronitrile isohexyl cyanide propenenitrile acrylonitrile

Two major resonance contributors in esters, carboxylic acids, and amides

Carboxylic acids have relatively high boiling points because Amides have the highest boiling points

The reactivity of carbonyl compounds resides in the polarity of the carbonyl group in a nucleophilic acyl substitution reaction Z– will be expelled if it is a much weaker base than Y– (k–1 >> k2) Y– will be expelled if it is a much weaker base (k2 >> k–1)

Reaction Coordinate Diagrams for Nucleophilic Acyl Substitution Reactions (a) the Nu– is a weaker base (b) the Nu– is a stronger base (c) the Nu– and the leaving group have similar basicities

A Molecular Orbital Description of How Carbonyl Compounds React

All carboxylic acid derivatives react by the same general mechanism The tetrahedral intermediate eliminates the weakest base

If the nucleophile is neutral …

Reactions of Acyl Halides

Formation of Amides from Acyl Halides Tertiary amines cannot form amides

Reactions of Acid Anhydrides Acid anhydrides do not react with sodium chloride or with sodium bromide

Reactions of Esters a hydrolysis reaction a transesterification

an aminolysis reaction

There are no negatively charged species in the reaction

Excess water will force the equilibrium to the right Alcohols that have low boiling points can be removed by distillation as they are formed

Acid catalyzes the reaction by …

Esters with tertiary alkyl groups undergo hydrolysis much more rapidly than do others

Hydroxide ion increases the rate of formation of the tetrahedral intermediate This reaction is not reversible

Elucidating the reaction mechanism of nucleophilic acyl substitution

Fats and Oils Are Triesters of Glycerol

Nucleophilic Acyl Substitution of Carboxylic Acids

Carboxylic acids do not undergo nucleophilic acyl substitution reactions with amines

Hydrolysis of Amides

Dehydration of an Amide Dehydration reagents commonly used are SOCl2, P2O5, or POCl3

An amide cannot be hydrolyzed without a catalyst An acid catalyst can make a group a better leaving group

Hydrolysis of an Imide The Gabriel Synthesis

Nitriles are harder to hydrolyze than amides

Designing the Synthesis of Cyclic Compounds Formation of lactones

Preparation of a compound with a ketone group attached to a benzene ring

Preparation of a cyclic ester

Activation of Carboxylic Acids

The goal is to convert the OH group into a better leaving group such that the acyl chloride can be prepared

The acyl halide can be used to prepare other carboxylic acid derivatives

Activated Carboxylic Acid Derivatives in Living Organisms

Dicarboxylic acids readily lose water when heated if they can form a cyclic anhydride with a five- or a six-membered ring