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Relative Reactivity of Carboxylic Acid

Derivatives1

Nucleophiles react more readily with unhindered carbony l groups

More electrophilic carbony l groups are more reactiv e to addition (acy l halides are most reactiv e, amides are least)

The intermediate with the best leav ing group decomposes f astest

Conversion of Carboxylic Acids into Acid

Chlorides2

Reaction with thiony l chloride, SOCl2

Mechanism of Thionyl Chloride Reaction

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Nucleophilic acy l substitution pathway

Carboxy lic acid is conv erted into a chlorosulfite

which then reacts with chloride

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Conversion of Carboxylic Acids into Acid

Anhydrides4

Acid anhy drides can be deriv ed f rom two molecules of carboxy lic acid by strong heating to remov e water

Conversion of Carboxylic Acids into

Esters5

Methods include reaction of a carboxy late anion with a primary alky l halide

Fischer Esterification6

Heating a carboxy lic acid in an alcohol solv ent

containing a small amount of strong acid produces an

ester f rom the alcohol and acid

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Mechanism of the Fischer Esterification

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The reaction is an acid-cataly zed, nucleophilic acy l substitution of a carboxy lic acid

When 18O-labeled methanol reacts with benzoic acid, the methy l benzoate produced is 18O-labeled but the water produced is unlabeled

Acid Halides8

Chemistry of Acid Halides9

Acid chlorides are prepared f rom carboxy lic acids by reaction with SOCl2

Reaction of a carboxy lic acid with PBr3 y ields the acid bromide

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Reactions of Acid Halides10

Nucleophilic acy l substitution

Halogen replaced by OH, by OR, or by NH2

Reduction y ields a primary alcohol

Grignard reagent y ields a tertiary alcohol

Hydrolysis: Conversion of Acid Halides

into Acids11

Acid chlorides react with water to y ield carboxy lic

acids

HCl is generated during the hy droly sis: a base is

added to remov e the HCl

Substitution in Synthesis12

We can readily conv ert a more reactiv e acid deriv ativ e into a less reactiv e one

Reactions in the opposite sense are possible but require more complex approaches

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Conversion of Acid Halides to Esters13

Esters are produced in the reaction of acid chlorides with alcohols in the presence of py ridine or NaOH. This is called Alcoholysis

The reaction is better with less steric bulk

Aminolysis: Conversion of Acid Halides

into Amides14

Amides result f rom the reaction of acid chlorides with

NH3, primary (RNH2) and secondary amines (R2NH)

The reaction with tertiary amines (R3N) giv es an

unstable species that cannot be isolated

HCl is neutralized by the amine or an added base

Reduction: Conversion of Acid Chlorides

into Alcohols15

LiAlH4 reduces acid chlorides to y ield aldehy des and

then primary alcohols

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Reaction of Acid Chlorides with Grignard

Reagent gives a 3º Alcohol16

Grignard reagents react with acid chlorides to y ield tertiary alcohols in which two of the substituents are the same

Formation of Ketones from Acid Chlorides

17

Reaction of an acid chloride with a lithium

diorganocopper (Gilman) reagent, Li+ R2Cu

Addition produces an acy l diorganocopper

intermediate, f ollowed by loss of R Cu and f ormation

of the ketone

Conversion of Acid halide to Acid

Anhydrides18

Prepared by nucleophilic acyl substitution of

a carboxylate w ith an acid chloride

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Reactions of Acid Anhydrides19

Similar to acid chlorides in reactivity

Acetylation20

Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines

Chemistry of Esters21

Many esters are pleasant-smelling liquids: f ragrant odors of f ruits and f lowers

Also present in f ats and v egetable oils

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Preparation of Esters22

Esters are usually prepared f rom carboxy lic acids

Reactions of Esters23

Less reactive tow ard nucleophiles than are

acid chlorides or anhydrides

Cyclic esters are called lactones and react

similarly to acyclic esters

Hydrolysis: Conversion of Esters into

Carboxylic Acids24

An ester is hy droly zed by aqueous base or aqueous acid to y ield a carboxy lic acid plus an alcohol

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Mechanism of Ester Hydrolysis25

Hy droxide cataly sis v ia an addition intermediate

Aminolysis of Esters26

Ammonia reacts with esters to f orm amides

Reduction: Conversion of Esters into

Alcohols27

Reaction with LiAlH4 y ields primary alcohols

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Mechanism of Reduction of Esters28

Hy dride ion adds to the carbony l group, f ollowed by

elimination of alkoxide ion to y ield an aldehy de

Reduction of the aldehy de giv es the primary alcohol

Reaction of Esters with Grignard

Reagents29

React with 2 equiv alents of a Grignard reagent to

y ield a tertiary alcohol

Chemistry of Amides30

Amides are abundant in all living

organisms…proteins, nucleic acids, and other

pharmaceuticals have amide functional groups

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Preparation of Amides31

Prepared by reaction of an acid chloride with ammonia, monosubstituted amines, or disubstituted amines

Reactions of Amides32

Heating in either aqueous acid or aqueous base produces a carboxy lic acid and amine

Acidic hy droly sis by nucleophilic addition of water to the protonated amide, f ollowed by loss of ammonia

Basic Hydrolysis of Amides33

Addition of hy droxide and loss of amide ion

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Reduction: Conversion of Amides into

Amines34

Reduced by LiAlH4 to an amine rather than an

alcohol

Conv erts C=O CH2

Mechanism of Reduction35

Addition of hy dride to carbony l group

Loss of the oxy gen as an aluminate anion to giv e an

iminium ion intermediate which is reduced to the

amine

Uses of Reduction of Amides36

Works with cy clic and acy clic

Good route to cy clic amines

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Conversion of Amide to Nitrile37

Reaction of primary amides RCONH2 with SOCl2 or

POCl3

Not limited by steric hindrance or side reactions (as is

the reaction of alky l halides with NaCN)

Mechanism of Dehydration of Amides38

Nucleophilic amide oxy gen atom attacks SOCl2f ollowed by deprotonation and elimination

Naming Carboxylic Acid

Derivatives

Thioesters, RCOSR’

Names similar to the corresponding esters

Prefix thio- is added to carboxylate if ester has a

common name

–oate or carboxylate is replaced by –thioate or

carbothioate if ester has a systematic name

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Chemistry of Thioesters and AcylPhosphates:

Biological Carboxylic Acid Derivatives40

Nucleophilic carboxyl

substitution in nature

often involves a

thioester or acyl

phosphate

Acetyl CoA’s are most

common thioesters in

nature