derivatives of carboxylic acids - … 4 introduction to nucleophilic acyl substitution leaving group...

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DERIVATIVES OF CARBOXYLIC ACIDS

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CARBOXYLIC ACID DERIVATIVES

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Introduction to Nucleophilic AcylSubstitution

leaving group

♦ Carboxylic acid derivatives (RCOZ) react with nucleophiles because they contain an electrophilic, unhindered carbonyl carbon.♦ Substitution occurs, not addition, because carboxylic acid derivatives (RCOZ) have a leaving group Z on the carbonyl carbon.

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The Mechanism

The general mechanism for nucleophilic acyl substitution is a two-step process: nucleophilic attack followed by loss of the leaving group.

The overall result of addition of a nucleophile and elimination of a leaving group is substitution of the nucleophile for the leaving group.

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Nucleophiles

Nucleophilic acyl substitution using heteroatomic nucleophiles results in the conversion of one carboxylic acid derivative into another.

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most reactive

CO

ClR

More reactive acyl compounds (acid chlorides and anhydrides) can be converted to less reactive ones (carboxylic acids, esters, and amide).

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Reactions of Acid Chloride

Cl-

Acid chlorides readily react with nucleophiles to form nucleophilic substitution products with HClusually formed as a reaction by-product. A weak base like pyridine is added to the reaction mixture to remove this strong acid, forming an ammonium salt.

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Acid chlorides react with oxygen nucleophiles to form anhydrides, carboxylic acids, and esters

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Mechanisms

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Acid chlorides also react with ammonia and 1o and 2o amines to form 1o, 2o, and 3o amides respectively. Two equivalents of NH3 or amine are used.

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(CH3CH2)2NH2Cl

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Review of other reactions of acid chlorides

1. Reduction to aldehydes

2. Conversion to ketones

3. Friedel-Crafts Acylation

R-COCl

Acid chloride

+ R'2CuLi R-CO-R'

Ketone

R-COCl

Acid chloride

+

Benzene

AlCl3

Acybenzene

COR

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Reactions of AnhydridesLess reactive than acid chlorides, anhydrides nonetheless readily react with most nucleophiles to form substitution products. Nucleophilicattack occurs at one carbonyl group, while the second carbonyl becomes part of the leaving group.

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16Anhydrides can't be used to make acid chlorides!

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Mechanism

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acetylsalicylic acid(aspirin)

acetaminophen (the active ingredient in Tylenol)

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-Heroin-

Acetylation of Morphine

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• Esters can be converted into carboxylic acids and amides.

Reactions of Esters

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Ester Hydrolysis in Aqueous Acid

The hydrolysis of esters in aqueous acid is a reversible equilibrium reaction that is driven to the right by using a large excess of water.

The first step in acid-catalyzed ester hydrolysis is protonation on oxygen, the same first step of any mechanism involving an oxygen-containing starting material and an acid.

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MechanismAcid-Catalyzed Hydrolysis of an Ester to a Carboxylic Acid

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Problem

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Ester Hydrolysis in Aqueous Base

Esters are hydrolyzed in aqueous base to form carboxylate anions. Basic hydrolysis of an ester is called saponification.

The mechanism for this reaction has the usual two steps of the general mechanism for nucleophilic acyl substitution—addition of the nucleophilefollowed by loss of a leaving group—plus an additional step involving proton transfer.

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MechanismBase-Promoted Hydrolysis of an Ester to a Carboxylic Acid

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Problem

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Saponification

The word saponification comes from the Latin “sapo” meaning soap. Soap is prepared by hydrolyzing esters in fats with aqueous base.

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Reactions of AmidesBecause amides have the poorest leaving group of all the carboxylic acid derivatives. They are the least reactive. In fact, they have only one useful reaction. Under strenuous reaction conditions, amides are hydrolyzed in acid or base to form carboxylic acids or carboxylate anion.

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Mechanism Amide Hydrolysis in Base

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Nitriles

Nitriles are readily prepared by SN2 substitution reactions of unhindered methyl and 1o alkyl halides with -CN. This reaction adds one carbon to the alkyl halide and forms a new carbon-carbon bond

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Hydrolysis of Nitriles

Nitriles are hydrolyzed with water in the presence of acid or base to yield carboxylic acids or carboxylate anions. In this reaction, the three C-N bonds are replaced by three C-0 bonds.

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Mechanism Hydrolysis of a Nitrile in Base

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Reduction of Nitriles

Nitriles are reduced with metal hydride reagents to form either 1o amines or aldehydes, depending on the reducing agent.

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Mechanism Reduction of a Nitrile with LiAIH4

Mechanism Reduction of a Nitrile with DIBAL-H

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Addition of Grignard and Organolithium Reagents to Nitriles

Both Grignard and organolithium reagents react with nitriles to form ketones with a new carbon-carbon bond.

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Mechanism Addition of Grignard and Organolithium Reagents (R-M) to Nitriles

PROBLEM: Draw the products of each reaction.