Carb Acid Deriv

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DERIVATIVES OF

CARBOXYLIC ACIDS

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CARBOXYLIC ACID DERIVATIVES

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Introduction to Nucleophilic Acyl

Substitution

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

C

O

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 HCl

usually 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 1

o

, 2

o

, and 3

o

amides respectively. Two equivalents of NH3 or amine are used.

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(CH3CH2)2NH2

Cl

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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 Anhydrides

Less reactive than acid chlorides, anhydrides nonetheless readily react

with most nucleophiles to form substitution products. Nucleophilic

attack occurs at one carbonyl group, while the second carbonyl

becomes part of the leaving group.

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Anhydrides 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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Mechanism

Acid-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 nucleophile

followed by loss of a leaving group—plus an additional step involving protontransfer.

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Mechanism

Base-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 acidderivatives. 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 unhinderedmethyl 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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MechanismAddition of Grignard and Organolithium Reagents (R-M)

to Nitriles

PROBLEM: Draw the products of each reaction.